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• Vaz, D.C., Rodrigues, J.R., Loureiro-Ferreira, N., Müller, T.D., Sebald, W., Redfield, C., and Brito, R.M.M. (2024) ‘Lessons on protein structure from interleukin-4: All disulfides are not created equal’, Proteins, 92(2), 219–235, available: https://doi.org/10.1002/prot.26611.
  • [ Abstract ]
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  Interleukin-4 (IL-4) is a hematopoietic cytokine composed by a four-helix bundle stabilized by an antiparallel beta-sheet and three disulfide bonds: Cys3-Cys127, Cys24-Cys65, and Cys46-Cys99. IL-4 is involved in several immune responses associated to infection, allergy, autoimmunity, and cancer. Besides its physiological relevance, IL-4 is often used as a "model" for protein design and engineering. Hence, to understand the role of each disulfide in the structure and dynamics of IL-4, we carried out several spectroscopic analyses (circular dichroism [CD], fluorescence, nuclear magnetic resonance [NMR]), and molecular dynamics (MD) simulations on wild-type IL-4 and four IL-4 disulfide mutants. All disulfide mutants showed loss of structure, altered interhelical angles, and looser core packings, showing that all disulfides are relevant for maintaining the overall fold and stability of the four-helix bundle motif, even at very low pH. In the absence of the disulfide connecting both protein termini Cys3-Cys127, C3T-IL4 showed a less packed protein core, loss of secondary structure (~9%) and fast motions on the sub-nanosecond time scale (lower S(2) order parameters and larger τ(c) correlation time), especially at the two protein termini, loops, beginning of helix A and end of helix D. In the absence of Cys24-Cys65, C24T-IL4 presented shorter alpha-helices (14% loss in helical content), altered interhelical angles, less propensity to form the small anti-parallel beta-sheet and increased dynamics. Simultaneously deprived of two disulfides (Cys3-Cys127 and Cys24-Cys65), IL-4 formed a partially folded "molten globule" with high 8-anilino-1-naphtalenesulphonic acid-binding affinity and considerable loss of secondary structure (~50%decrease), as shown by the far UV-CD, NMR, and MD data.

  @article{vaz2024lessons, abstract = {Interleukin-4 (IL-4) is a hematopoietic cytokine composed by a four-helix bundle stabilized by an antiparallel beta-sheet and three disulfide bonds: Cys3-Cys127, Cys24-Cys65, and Cys46-Cys99. IL-4 is involved in several immune responses associated to infection, allergy, autoimmunity, and cancer. Besides its physiological relevance, IL-4 is often used as a "model" for protein design and engineering. Hence, to understand the role of each disulfide in the structure and dynamics of IL-4, we carried out several spectroscopic analyses (circular dichroism [CD], fluorescence, nuclear magnetic resonance [NMR]), and molecular dynamics (MD) simulations on wild-type IL-4 and four IL-4 disulfide mutants. All disulfide mutants showed loss of structure, altered interhelical angles, and looser core packings, showing that all disulfides are relevant for maintaining the overall fold and stability of the four-helix bundle motif, even at very low pH. In the absence of the disulfide connecting both protein termini Cys3-Cys127, C3T-IL4 showed a less packed protein core, loss of secondary structure ( 9%) and fast motions on the sub-nanosecond time scale (lower S(2) order parameters and larger τ(c) correlation time), especially at the two protein termini, loops, beginning of helix A and end of helix D. In the absence of Cys24-Cys65, C24T-IL4 presented shorter alpha-helices (14% loss in helical content), altered interhelical angles, less propensity to form the small anti-parallel beta-sheet and increased dynamics. Simultaneously deprived of two disulfides (Cys3-Cys127 and Cys24-Cys65), IL-4 formed a partially folded "molten globule" with high 8-anilino-1-naphtalenesulphonic acid-binding affinity and considerable loss of secondary structure ( 50%decrease), as shown by the far UV-CD, NMR, and MD data.}, address = {United States}, author = {Vaz, Daniela C and Rodrigues, J Rui and Loureiro-Ferreira, Nuno and Müller, Thomas D and Sebald, Walter and Redfield, Christina and Brito, Rui M M}, journal = {Proteins}, keywords = {myown}, month = {02}, number = 2, pages = {219–235}, title = {Lessons on protein structure from interleukin-4: All disulfides are not created equal}, volume = 92, year = 2024 }

  %0 Journal Article %1 vaz2024lessons %A Vaz, Daniela C %A Rodrigues, J Rui %A Loureiro-Ferreira, Nuno %A Müller, Thomas D %A Sebald, Walter %A Redfield, Christina %A Brito, Rui M M %C United States %D 2024 %J Proteins %N 2 %P 219--235 %R 10.1002/prot.26611 %T Lessons on protein structure from interleukin-4: All disulfides are not created equal %U https://pubmed.ncbi.nlm.nih.gov/37814578 %V 92 %X Interleukin-4 (IL-4) is a hematopoietic cytokine composed by a four-helix bundle stabilized by an antiparallel beta-sheet and three disulfide bonds: Cys3-Cys127, Cys24-Cys65, and Cys46-Cys99. IL-4 is involved in several immune responses associated to infection, allergy, autoimmunity, and cancer. Besides its physiological relevance, IL-4 is often used as a "model" for protein design and engineering. Hence, to understand the role of each disulfide in the structure and dynamics of IL-4, we carried out several spectroscopic analyses (circular dichroism [CD], fluorescence, nuclear magnetic resonance [NMR]), and molecular dynamics (MD) simulations on wild-type IL-4 and four IL-4 disulfide mutants. All disulfide mutants showed loss of structure, altered interhelical angles, and looser core packings, showing that all disulfides are relevant for maintaining the overall fold and stability of the four-helix bundle motif, even at very low pH. In the absence of the disulfide connecting both protein termini Cys3-Cys127, C3T-IL4 showed a less packed protein core, loss of secondary structure (~9%) and fast motions on the sub-nanosecond time scale (lower S(2) order parameters and larger τ(c) correlation time), especially at the two protein termini, loops, beginning of helix A and end of helix D. In the absence of Cys24-Cys65, C24T-IL4 presented shorter alpha-helices (14% loss in helical content), altered interhelical angles, less propensity to form the small anti-parallel beta-sheet and increased dynamics. Simultaneously deprived of two disulfides (Cys3-Cys127 and Cys24-Cys65), IL-4 formed a partially folded "molten globule" with high 8-anilino-1-naphtalenesulphonic acid-binding affinity and considerable loss of secondary structure (~50%decrease), as shown by the far UV-CD, NMR, and MD data.

• Thomas, S., Fiebig, J.E., Kuhn, E.-M., Mayer, D.S., Filbeck, S., Schmitz, W., Krischke, M., Gropp, R., and Mueller, T.D. (2023) ‘Design of Glycoengineered IL-4 Antagonists Employing Chemical and Biosynthetic Glycosylation’, ACS omega, 8(28), 24841–24852, available: https://doi.org/10.1021/acsomega.3c00726.
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  Interleukin-4 (IL-4) plays a key role in atopic diseases. It coordinates T-helper cell differentiation to subtype 2, thereby directing defense toward humoral immunity. Together with Interleukin-13, IL-4 further induces immunoglobulin class switch to IgE. Antibodies of this type activate mast cells and basophilic and eosinophilic granulocytes, which release pro-inflammatory mediators accounting for the typical symptoms of atopic diseases. IL-4 and IL-13 are thus major targets for pharmaceutical intervention strategies to treat atopic diseases. Besides neutralizing antibodies against IL-4, IL-13, or its receptors, IL-4 antagonists can present valuable alternatives. Pitrakinra, an Escherichia coli-derived IL-4 antagonist, has been evaluated in clinical trials for asthma treatment in the past; however, deficits such as short serum lifetime and potential immunogenicity among others stopped further development. To overcome such deficits, PEGylation of therapeutically important proteins has been used to increase the lifetime and proteolytic stability. As an alternative, glycoengineering is an emerging strategy used to improve pharmacokinetics of protein therapeutics. In this study, we have established different strategies to attach glycan moieties to defined positions in IL-4. Different chemical attachment strategies employing thiol chemistry were used to attach a glucose molecule at amino acid position 121, thereby converting IL-4 into a highly effective antagonist. To enhance the proteolytic stability of this IL-4 antagonist, additional glycan structures were introduced by glycoengineering utilizing eucaryotic expression. IL-4 antagonists with a combination of chemical and biosynthetic glycoengineering could be useful as therapeutic alternatives to IL-4 neutralizing antibodies already used to treat atopic diseases.

  @article{thomas2023design, abstract = {Interleukin-4 (IL-4) plays a key role in atopic diseases. It coordinates T-helper cell differentiation to subtype 2, thereby directing defense toward humoral immunity. Together with Interleukin-13, IL-4 further induces immunoglobulin class switch to IgE. Antibodies of this type activate mast cells and basophilic and eosinophilic granulocytes, which release pro-inflammatory mediators accounting for the typical symptoms of atopic diseases. IL-4 and IL-13 are thus major targets for pharmaceutical intervention strategies to treat atopic diseases. Besides neutralizing antibodies against IL-4, IL-13, or its receptors, IL-4 antagonists can present valuable alternatives. Pitrakinra, an Escherichia coli-derived IL-4 antagonist, has been evaluated in clinical trials for asthma treatment in the past; however, deficits such as short serum lifetime and potential immunogenicity among others stopped further development. To overcome such deficits, PEGylation of therapeutically important proteins has been used to increase the lifetime and proteolytic stability. As an alternative, glycoengineering is an emerging strategy used to improve pharmacokinetics of protein therapeutics. In this study, we have established different strategies to attach glycan moieties to defined positions in IL-4. Different chemical attachment strategies employing thiol chemistry were used to attach a glucose molecule at amino acid position 121, thereby converting IL-4 into a highly effective antagonist. To enhance the proteolytic stability of this IL-4 antagonist, additional glycan structures were introduced by glycoengineering utilizing eucaryotic expression. IL-4 antagonists with a combination of chemical and biosynthetic glycoengineering could be useful as therapeutic alternatives to IL-4 neutralizing antibodies already used to treat atopic diseases.}, address = {United States}, author = {Thomas, Sarah and Fiebig, Juliane E and Kuhn, Eva-Maria and Mayer, Dominik S and Filbeck, Sebastian and Schmitz, Werner and Krischke, Markus and Gropp, Roswitha and Mueller, Thomas D}, journal = {ACS omega}, keywords = {myown}, month = {07}, number = 28, pages = {24841–24852}, title = {Design of Glycoengineered IL-4 Antagonists Employing Chemical and Biosynthetic Glycosylation}, volume = 8, year = 2023 }

  %0 Journal Article %1 thomas2023design %A Thomas, Sarah %A Fiebig, Juliane E %A Kuhn, Eva-Maria %A Mayer, Dominik S %A Filbeck, Sebastian %A Schmitz, Werner %A Krischke, Markus %A Gropp, Roswitha %A Mueller, Thomas D %C United States %D 2023 %J ACS omega %N 28 %P 24841--24852 %R 10.1021/acsomega.3c00726 %T Design of Glycoengineered IL-4 Antagonists Employing Chemical and Biosynthetic Glycosylation %U https://pubmed.ncbi.nlm.nih.gov/37483220 %V 8 %X Interleukin-4 (IL-4) plays a key role in atopic diseases. It coordinates T-helper cell differentiation to subtype 2, thereby directing defense toward humoral immunity. Together with Interleukin-13, IL-4 further induces immunoglobulin class switch to IgE. Antibodies of this type activate mast cells and basophilic and eosinophilic granulocytes, which release pro-inflammatory mediators accounting for the typical symptoms of atopic diseases. IL-4 and IL-13 are thus major targets for pharmaceutical intervention strategies to treat atopic diseases. Besides neutralizing antibodies against IL-4, IL-13, or its receptors, IL-4 antagonists can present valuable alternatives. Pitrakinra, an Escherichia coli-derived IL-4 antagonist, has been evaluated in clinical trials for asthma treatment in the past; however, deficits such as short serum lifetime and potential immunogenicity among others stopped further development. To overcome such deficits, PEGylation of therapeutically important proteins has been used to increase the lifetime and proteolytic stability. As an alternative, glycoengineering is an emerging strategy used to improve pharmacokinetics of protein therapeutics. In this study, we have established different strategies to attach glycan moieties to defined positions in IL-4. Different chemical attachment strategies employing thiol chemistry were used to attach a glucose molecule at amino acid position 121, thereby converting IL-4 into a highly effective antagonist. To enhance the proteolytic stability of this IL-4 antagonist, additional glycan structures were introduced by glycoengineering utilizing eucaryotic expression. IL-4 antagonists with a combination of chemical and biosynthetic glycoengineering could be useful as therapeutic alternatives to IL-4 neutralizing antibodies already used to treat atopic diseases.
• Steiert, F., Schultz, P., Hoefinger, S., Mueller, T.D., Schwille, P., and Weidemann, T. (2023) ‘Insights into receptor structure and dynamics at the surface of living cells’, Nature Communications, 14(1596), 15, available: https://doi.org/doi: 10.1038/s41467-023-37284-4.
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  Evaluating protein structures in living cells remains a challenge. Here, we investigate Interleukin-4 receptor alpha (IL-4Rα) into which the non-canonical amino acid bicyclo[6.1.0]nonyne-lysine (BCNK) is incorporated by genetic code expansion. Bioorthogonal click labeling is performed with tetrazine-conjugated dyes. To quantify the reaction yield in situ, we develop brightness-calibrated ratiometric imaging, a protocol where fluorescent signals in confocal multi-color images are ascribed to local concentrations. Screening receptor mutants bearing BCNK in the extracellular domain uncovered site-specific variations of both click efficiency and Interleukin-4 binding affinity, indicating subtle well-defined structural perturbations. Molecular dynamics and continuum electrostatics calculations suggest solvent polarization to determine site-specific variations of BCNK reactivity. Strikingly, signatures of differential click efficiency, measured for IL-4Rα in ligand-bound and free form, mirror sub-angstrom deformations of the protein backbone at corresponding locations. Thus, click efficiency by itself represents a remarkably informative readout linked to protein structure and dynamics in the native plasma membrane.

  @article{noauthororeditor, abstract = {Evaluating protein structures in living cells remains a challenge. Here, we investigate Interleukin-4 receptor alpha (IL-4Rα) into which the non-canonical amino acid bicyclo[6.1.0]nonyne-lysine (BCNK) is incorporated by genetic code expansion. Bioorthogonal click labeling is performed with tetrazine-conjugated dyes. To quantify the reaction yield in situ, we develop brightness-calibrated ratiometric imaging, a protocol where fluorescent signals in confocal multi-color images are ascribed to local concentrations. Screening receptor mutants bearing BCNK in the extracellular domain uncovered site-specific variations of both click efficiency and Interleukin-4 binding affinity, indicating subtle well-defined structural perturbations. Molecular dynamics and continuum electrostatics calculations suggest solvent polarization to determine site-specific variations of BCNK reactivity. Strikingly, signatures of differential click efficiency, measured for IL-4Rα in ligand-bound and free form, mirror sub-angstrom deformations of the protein backbone at corresponding locations. Thus, click efficiency by itself represents a remarkably informative readout linked to protein structure and dynamics in the native plasma membrane.}, author = {Steiert, Frederik and Schultz, Peter and Hoefinger, Siegfried and Mueller, Thomas D. and Schwille, Petra and Weidemann, Thomas}, journal = {Nature Communications}, keywords = {own}, month = {03}, number = 1596, pages = 15, title = {Insights into receptor structure and dynamics at the surface of living cells}, volume = 14, year = 2023 }

  %0 Journal Article %1 noauthororeditor %A Steiert, Frederik %A Schultz, Peter %A Hoefinger, Siegfried %A Mueller, Thomas D. %A Schwille, Petra %A Weidemann, Thomas %D 2023 %J Nature Communications %N 1596 %P 15 %R doi: 10.1038/s41467-023-37284-4 %T Insights into receptor structure and dynamics at the surface of living cells %U https://www.nature.com/articles/s41467-023-37284-4 %V 14 %X Evaluating protein structures in living cells remains a challenge. Here, we investigate Interleukin-4 receptor alpha (IL-4Rα) into which the non-canonical amino acid bicyclo[6.1.0]nonyne-lysine (BCNK) is incorporated by genetic code expansion. Bioorthogonal click labeling is performed with tetrazine-conjugated dyes. To quantify the reaction yield in situ, we develop brightness-calibrated ratiometric imaging, a protocol where fluorescent signals in confocal multi-color images are ascribed to local concentrations. Screening receptor mutants bearing BCNK in the extracellular domain uncovered site-specific variations of both click efficiency and Interleukin-4 binding affinity, indicating subtle well-defined structural perturbations. Molecular dynamics and continuum electrostatics calculations suggest solvent polarization to determine site-specific variations of BCNK reactivity. Strikingly, signatures of differential click efficiency, measured for IL-4Rα in ligand-bound and free form, mirror sub-angstrom deformations of the protein backbone at corresponding locations. Thus, click efficiency by itself represents a remarkably informative readout linked to protein structure and dynamics in the native plasma membrane.
• Hedrich, R., Müller, T.D., Marten, I., and Becker, D. (2023) ‘TPC1 vacuole SV channel gains further shape – voltage priming of calcium-dependent gating’, Trends in Plant Science, 28(6), 673–684, available: https://doi.org/https://doi.org/10.1016/j.tplants.2023.01.001.
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  Across phyla, voltage-gated ion channels (VGICs) allow excitability. The vacuolar two-pore channel AtTPC1 from the tiny mustard plant Arabidopsis thaliana has emerged as a paradigm for deciphering the role of voltage and calcium signals in membrane excitation. Among the numerous experimentally determined structures of VGICs, AtTPC1 was the first to be revealed in a closed and resting state, fueling speculation about structural rearrangements during channel activation. Two independent reports on the structure of a partially opened AtTPC1 channel protein have led to working models that offer promising insights into the molecular switches associated with the gating process. We review new structure–function models and also discuss the evolutionary impact of two-pore channels (TPCs) on K+ homeostasis and vacuolar excitability.

  @article{HEDRICH2023673, abstract = {Across phyla, voltage-gated ion channels (VGICs) allow excitability. The vacuolar two-pore channel AtTPC1 from the tiny mustard plant Arabidopsis thaliana has emerged as a paradigm for deciphering the role of voltage and calcium signals in membrane excitation. Among the numerous experimentally determined structures of VGICs, AtTPC1 was the first to be revealed in a closed and resting state, fueling speculation about structural rearrangements during channel activation. Two independent reports on the structure of a partially opened AtTPC1 channel protein have led to working models that offer promising insights into the molecular switches associated with the gating process. We review new structure–function models and also discuss the evolutionary impact of two-pore channels (TPCs) on K+ homeostasis and vacuolar excitability.}, author = {Hedrich, Rainer and Müller, Thomas D. and Marten, Irene and Becker, Dirk}, journal = {Trends in Plant Science}, keywords = {myown}, number = 6, pages = {673-684}, title = {TPC1 vacuole SV channel gains further shape – voltage priming of calcium-dependent gating}, volume = 28, year = 2023 }

  %0 Journal Article %1 HEDRICH2023673 %A Hedrich, Rainer %A Müller, Thomas D. %A Marten, Irene %A Becker, Dirk %D 2023 %J Trends in Plant Science %N 6 %P 673-684 %R https://doi.org/10.1016/j.tplants.2023.01.001 %T TPC1 vacuole SV channel gains further shape – voltage priming of calcium-dependent gating %U https://www.sciencedirect.com/science/article/pii/S1360138523000201 %V 28 %X Across phyla, voltage-gated ion channels (VGICs) allow excitability. The vacuolar two-pore channel AtTPC1 from the tiny mustard plant Arabidopsis thaliana has emerged as a paradigm for deciphering the role of voltage and calcium signals in membrane excitation. Among the numerous experimentally determined structures of VGICs, AtTPC1 was the first to be revealed in a closed and resting state, fueling speculation about structural rearrangements during channel activation. Two independent reports on the structure of a partially opened AtTPC1 channel protein have led to working models that offer promising insights into the molecular switches associated with the gating process. We review new structure–function models and also discuss the evolutionary impact of two-pore channels (TPCs) on K+ homeostasis and vacuolar excitability.
• Swinerd, G.W., Alhussini, A.A., Sczelecki, S., Heath, D., Mueller, T.D., McNatty, K.P., and Pitman, J.L. (2023) ‘Molecular forms of BMP15 and GDF9 in mammalian species that differ in litter size’, Scientific reports, 13(1), 22428–22428, available: https://doi.org/10.1038/s41598-023-49852-1.
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  Bone morphogenetic protein (BMP15) and growth differentiation factor (GDF9) are critical for ovarian follicular development and fertility and are associated with litter size in mammals. These proteins initially exist as pre-pro-mature proteins, that are subsequently cleaved into biologically active forms. Thus, the molecular forms of GDF9 and BMP15 may provide the key to understanding the differences in litter size determination in mammals. Herein, we compared GDF9 and BMP15 forms in mammals with high (pigs) and low to moderate (sheep) and low (red deer) ovulation-rate. In all species, oocyte lysates and secretions contained both promature and mature forms of BMP15 and GDF9. Whilst promature and mature GDF9 levels were similar between species, deer produced more BMP15 and exhibited, together with sheep, a higher promature:mature BMP15 ratio. N-linked glycosylation was prominant in proregion and mature GDF9 and in proregion BMP15 of pigs, and present in proregion GDF9 of sheep. There was no evidence of secreted native homo- or hetero-dimers although a GDF9 dimer in red deer oocyte lysate was detected. In summary, GDF9 appeared to be equally important in all species regardless of litter size, whilst BMP15 levels were highest in strict monovulatory species.

  @article{swinerd2023molecular, abstract = {Bone morphogenetic protein (BMP15) and growth differentiation factor (GDF9) are critical for ovarian follicular development and fertility and are associated with litter size in mammals. These proteins initially exist as pre-pro-mature proteins, that are subsequently cleaved into biologically active forms. Thus, the molecular forms of GDF9 and BMP15 may provide the key to understanding the differences in litter size determination in mammals. Herein, we compared GDF9 and BMP15 forms in mammals with high (pigs) and low to moderate (sheep) and low (red deer) ovulation-rate. In all species, oocyte lysates and secretions contained both promature and mature forms of BMP15 and GDF9. Whilst promature and mature GDF9 levels were similar between species, deer produced more BMP15 and exhibited, together with sheep, a higher promature:mature BMP15 ratio. N-linked glycosylation was prominant in proregion and mature GDF9 and in proregion BMP15 of pigs, and present in proregion GDF9 of sheep. There was no evidence of secreted native homo- or hetero-dimers although a GDF9 dimer in red deer oocyte lysate was detected. In summary, GDF9 appeared to be equally important in all species regardless of litter size, whilst BMP15 levels were highest in strict monovulatory species.}, address = {England}, author = {Swinerd, Gene W and Alhussini, Abdulaziz A and Sczelecki, Sarah and Heath, Derek and Mueller, Thomas D and McNatty, Kenneth P and Pitman, Janet L}, journal = {Scientific reports}, keywords = {myown}, month = 12, number = 1, pages = {22428–22428}, title = {Molecular forms of BMP15 and GDF9 in mammalian species that differ in litter size}, volume = 13, year = 2023 }

  %0 Journal Article %1 swinerd2023molecular %A Swinerd, Gene W %A Alhussini, Abdulaziz A %A Sczelecki, Sarah %A Heath, Derek %A Mueller, Thomas D %A McNatty, Kenneth P %A Pitman, Janet L %C England %D 2023 %J Scientific reports %N 1 %P 22428--22428 %R 10.1038/s41598-023-49852-1 %T Molecular forms of BMP15 and GDF9 in mammalian species that differ in litter size %U https://pubmed.ncbi.nlm.nih.gov/38104237 %V 13 %X Bone morphogenetic protein (BMP15) and growth differentiation factor (GDF9) are critical for ovarian follicular development and fertility and are associated with litter size in mammals. These proteins initially exist as pre-pro-mature proteins, that are subsequently cleaved into biologically active forms. Thus, the molecular forms of GDF9 and BMP15 may provide the key to understanding the differences in litter size determination in mammals. Herein, we compared GDF9 and BMP15 forms in mammals with high (pigs) and low to moderate (sheep) and low (red deer) ovulation-rate. In all species, oocyte lysates and secretions contained both promature and mature forms of BMP15 and GDF9. Whilst promature and mature GDF9 levels were similar between species, deer produced more BMP15 and exhibited, together with sheep, a higher promature:mature BMP15 ratio. N-linked glycosylation was prominant in proregion and mature GDF9 and in proregion BMP15 of pigs, and present in proregion GDF9 of sheep. There was no evidence of secreted native homo- or hetero-dimers although a GDF9 dimer in red deer oocyte lysate was detected. In summary, GDF9 appeared to be equally important in all species regardless of litter size, whilst BMP15 levels were highest in strict monovulatory species.

• Siverino, C., Fahmy-Garcia, S., Mumcuoglu, D., Oberwinkler, H., Muehlemann, M., Mueller, T., Farrell, E., van Osch, G.J.V.M., and Nickel, J. (2022) ‘Site-Directed Immobilization of an Engineered Bone Morphogenetic Protein 2 ({BMP}2) Variant to Collagen-Based Microspheres Induces Bone Formation In Vivo’, International Journal of Molecular Sciences, 23(7), 3928, available: https://doi.org/10.3390/ijms23073928.
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  @article{Siverino_2022, author = {Siverino, Claudia and Fahmy-Garcia, Shorouk and Mumcuoglu, Didem and Oberwinkler, Heike and Muehlemann, Markus and Mueller, Thomas and Farrell, Eric and van Osch, Gerjo J. V. M. and Nickel, Joachim}, journal = {International Journal of Molecular Sciences}, keywords = {tdmueller}, month = {04}, number = 7, pages = 3928, publisher = {{MDPI} {AG}}, title = {Site-Directed Immobilization of an Engineered Bone Morphogenetic Protein 2 ({BMP}2) Variant to Collagen-Based Microspheres Induces Bone Formation In Vivo}, volume = 23, year = 2022 }

  %0 Journal Article %1 Siverino_2022 %A Siverino, Claudia %A Fahmy-Garcia, Shorouk %A Mumcuoglu, Didem %A Oberwinkler, Heike %A Muehlemann, Markus %A Mueller, Thomas %A Farrell, Eric %A van Osch, Gerjo J. V. M. %A Nickel, Joachim %D 2022 %I {MDPI} {AG} %J International Journal of Molecular Sciences %N 7 %P 3928 %R 10.3390/ijms23073928 %T Site-Directed Immobilization of an Engineered Bone Morphogenetic Protein 2 ({BMP}2) Variant to Collagen-Based Microspheres Induces Bone Formation In Vivo %U https://doi.org/10.3390%2Fijms23073928 %V 23
• Bertho, S., Herpin, A., Jouanno, E., Yano, A., Bobe, J., Parrinello, H., Journot, L., Guyomard, R., Muller, T., Swanson, P., McKinney, G., Williamson, K., Meek, M., Schartl, M., and Guiguen, Y. (2022) ‘A nonfunctional copy of the salmonid sex-determining gene (sdY) is responsible for the “apparent” XY females in Chinook salmon, Oncorhynchus tshawytscha’, G3 (Bethesda, Md.), 12(2), jkab451-, available: https://doi.org/10.1093/g3journal/jkab451.
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  Many salmonids have a male heterogametic (XX/XY) sex determination system, and they are supposed to have a conserved master sex-determining gene (sdY) that interacts at the protein level with Foxl2 leading to the blockage of the synergistic induction of Foxl2 and Nr5a1 of the cyp19a1a promoter. However, this hypothesis of a conserved master sex-determining role of sdY in salmonids is challenged by a few exceptions, one of them being the presence of naturally occurring "apparent" XY Chinook salmon, Oncorhynchus tshawytscha, females. Here, we show that some XY Chinook salmon females have a sdY gene (sdY-N183), with 1 missense mutation leading to a substitution of a conserved isoleucine to an asparagine (I183N). In contrast, Chinook salmon males have both a nonmutated sdY-I183 gene and the missense mutation sdY-N183 gene. The 3-dimensional model of SdY-I183N predicts that the I183N hydrophobic to hydrophilic amino acid change leads to a modification in the SdY β-sandwich structure. Using in vitro cell transfection assays, we found that SdY-I183N, like the wild-type SdY, is preferentially localized in the cytoplasm. However, compared to wild-type SdY, SdY-I183N is more prone to degradation, its nuclear translocation by Foxl2 is reduced, and SdY-I183N is unable to significantly repress the synergistic Foxl2/Nr5a1 induction of the cyp19a1a promoter. Altogether, our results suggest that the sdY-N183 gene of XY Chinook females is nonfunctional and that SdY-I183N is no longer able to promote testicular differentiation by impairing the synthesis of estrogens in the early differentiating gonads of wild Chinook salmon XY females.

  @article{bertho2022nonfunctional, abstract = {Many salmonids have a male heterogametic (XX/XY) sex determination system, and they are supposed to have a conserved master sex-determining gene (sdY) that interacts at the protein level with Foxl2 leading to the blockage of the synergistic induction of Foxl2 and Nr5a1 of the cyp19a1a promoter. However, this hypothesis of a conserved master sex-determining role of sdY in salmonids is challenged by a few exceptions, one of them being the presence of naturally occurring "apparent" XY Chinook salmon, Oncorhynchus tshawytscha, females. Here, we show that some XY Chinook salmon females have a sdY gene (sdY-N183), with 1 missense mutation leading to a substitution of a conserved isoleucine to an asparagine (I183N). In contrast, Chinook salmon males have both a nonmutated sdY-I183 gene and the missense mutation sdY-N183 gene. The 3-dimensional model of SdY-I183N predicts that the I183N hydrophobic to hydrophilic amino acid change leads to a modification in the SdY β-sandwich structure. Using in vitro cell transfection assays, we found that SdY-I183N, like the wild-type SdY, is preferentially localized in the cytoplasm. However, compared to wild-type SdY, SdY-I183N is more prone to degradation, its nuclear translocation by Foxl2 is reduced, and SdY-I183N is unable to significantly repress the synergistic Foxl2/Nr5a1 induction of the cyp19a1a promoter. Altogether, our results suggest that the sdY-N183 gene of XY Chinook females is nonfunctional and that SdY-I183N is no longer able to promote testicular differentiation by impairing the synthesis of estrogens in the early differentiating gonads of wild Chinook salmon XY females.}, address = {England}, author = {Bertho, Sylvain and Herpin, Amaury and Jouanno, Elodie and Yano, Ayaka and Bobe, Julien and Parrinello, Hugues and Journot, Laurent and Guyomard, René and Muller, Thomas and Swanson, Penny and McKinney, Garrett and Williamson, Kevin and Meek, Mariah and Schartl, Manfred and Guiguen, Yann}, journal = {G3 (Bethesda, Md.)}, keywords = {myown}, month = {02}, number = 2, pages = {jkab451–}, title = {A nonfunctional copy of the salmonid sex-determining gene (sdY) is responsible for the "apparent" XY females in Chinook salmon, Oncorhynchus tshawytscha}, volume = 12, year = 2022 }

  %0 Journal Article %1 bertho2022nonfunctional %A Bertho, Sylvain %A Herpin, Amaury %A Jouanno, Elodie %A Yano, Ayaka %A Bobe, Julien %A Parrinello, Hugues %A Journot, Laurent %A Guyomard, René %A Muller, Thomas %A Swanson, Penny %A McKinney, Garrett %A Williamson, Kevin %A Meek, Mariah %A Schartl, Manfred %A Guiguen, Yann %C England %D 2022 %J G3 (Bethesda, Md.) %N 2 %P jkab451-- %R 10.1093/g3journal/jkab451 %T A nonfunctional copy of the salmonid sex-determining gene (sdY) is responsible for the "apparent" XY females in Chinook salmon, Oncorhynchus tshawytscha %U https://pubmed.ncbi.nlm.nih.gov/35100376 %V 12 %X Many salmonids have a male heterogametic (XX/XY) sex determination system, and they are supposed to have a conserved master sex-determining gene (sdY) that interacts at the protein level with Foxl2 leading to the blockage of the synergistic induction of Foxl2 and Nr5a1 of the cyp19a1a promoter. However, this hypothesis of a conserved master sex-determining role of sdY in salmonids is challenged by a few exceptions, one of them being the presence of naturally occurring "apparent" XY Chinook salmon, Oncorhynchus tshawytscha, females. Here, we show that some XY Chinook salmon females have a sdY gene (sdY-N183), with 1 missense mutation leading to a substitution of a conserved isoleucine to an asparagine (I183N). In contrast, Chinook salmon males have both a nonmutated sdY-I183 gene and the missense mutation sdY-N183 gene. The 3-dimensional model of SdY-I183N predicts that the I183N hydrophobic to hydrophilic amino acid change leads to a modification in the SdY β-sandwich structure. Using in vitro cell transfection assays, we found that SdY-I183N, like the wild-type SdY, is preferentially localized in the cytoplasm. However, compared to wild-type SdY, SdY-I183N is more prone to degradation, its nuclear translocation by Foxl2 is reduced, and SdY-I183N is unable to significantly repress the synergistic Foxl2/Nr5a1 induction of the cyp19a1a promoter. Altogether, our results suggest that the sdY-N183 gene of XY Chinook females is nonfunctional and that SdY-I183N is no longer able to promote testicular differentiation by impairing the synthesis of estrogens in the early differentiating gonads of wild Chinook salmon XY females.

• Lehmann, J., J{o}rgensen, M.E., Fratz, S., Müller, H.M., Kusch, J., Scherzer, S., Navarro-Retamal, C., Mayer, D., Böhm, J., Konrad, K.R., Terpitz, U., Dreyer, I., Mueller, T.D., Sauer, M., Hedrich, R., Geiger, D., and Maierhofer, T. (2021) ‘Acidosis-induced activation of anion channel {SLAH}3 in the flooding-related stress response of Arabidopsis’, Current Biology, 31(16), 3575–3585.e9, available: https://doi.org/10.1016/j.cub.2021.06.018.
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  @article{Lehmann_2021, author = {Lehmann, Julian and J{\o}rgensen, Morten E. and Fratz, Stefanie and Müller, Heike M. and Kusch, Jana and Scherzer, Sönke and Navarro-Retamal, Carlos and Mayer, Dominik and Böhm, Jennifer and Konrad, Kai R. and Terpitz, Ulrich and Dreyer, Ingo and Mueller, Thomas D. and Sauer, Markus and Hedrich, Rainer and Geiger, Dietmar and Maierhofer, Tobias}, journal = {Current Biology}, keywords = {tdmueller}, month = {08}, number = 16, pages = {3575–3585.e9}, publisher = {Elsevier {BV}}, title = {Acidosis-induced activation of anion channel {SLAH}3 in the flooding-related stress response of Arabidopsis}, volume = 31, year = 2021 }

  %0 Journal Article %1 Lehmann_2021 %A Lehmann, Julian %A J{o}rgensen, Morten E. %A Fratz, Stefanie %A Müller, Heike M. %A Kusch, Jana %A Scherzer, Sönke %A Navarro-Retamal, Carlos %A Mayer, Dominik %A Böhm, Jennifer %A Konrad, Kai R. %A Terpitz, Ulrich %A Dreyer, Ingo %A Mueller, Thomas D. %A Sauer, Markus %A Hedrich, Rainer %A Geiger, Dietmar %A Maierhofer, Tobias %D 2021 %I Elsevier {BV} %J Current Biology %N 16 %P 3575--3585.e9 %R 10.1016/j.cub.2021.06.018 %T Acidosis-induced activation of anion channel {SLAH}3 in the flooding-related stress response of Arabidopsis %U https://doi.org/10.1016%2Fj.cub.2021.06.018 %V 31
• Heinks, T., Hettwer, A., Hiepen, C., Weise, C., Gorka, M., Knaus, P., Mueller, T.D., and Loidl-Stahlhofen, A. (2021) ‘Optimized expression and purification of a soluble BMP2 variant based on in-silico design’, Protein Expression and Purification, 186, 105918, available: https://doi.org/https://doi.org/10.1016/j.pep.2021.105918.
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  Bone morphogenetic protein 2 (BMP21) is a highly interesting therapeutic growth factor due to its strong osteogenic/osteoinductive potential. However, its pronounced aggregation tendency renders recombinant and soluble production troublesome and complex. While prokaryotic expression systems can provide BMP2 in large amounts, the typically insoluble protein requires complex denaturation-renaturation procedures with medically hazardous reagents to obtain natively folded homodimeric BMP2. Based on a detailed aggregation analysis of wildtype BMP2, we designed a hydrophilic variant of BMP2 additionally containing an improved heparin binding site (BMP2-2Hep-7M). Consecutive optimization of BMP2-2Hep-7M expression and purification enabled production of soluble dimeric BMP2-2Hep-7M in high yield in E. coli. This was achieved by a) increasing protein hydrophilicity via introducing seven point mutations within aggregation hot spots of wildtype BMP2 and a longer N-terminus resulting in higher affinity for heparin, b) by employing E. coli strain SHuffle® T7, which enables the structurally essential disulfide-bond formation in BMP2 in the cytoplasm, c) by using BMP2 variant characteristic soluble expression conditions and application of l-arginine as solubility enhancer. The BMP2 variant BMP2-2Hep-7M shows strongly attenuated although not completely eliminated aggregation tendency.

  @article{HEINKS2021105918, abstract = {Bone morphogenetic protein 2 (BMP21) is a highly interesting therapeutic growth factor due to its strong osteogenic/osteoinductive potential. However, its pronounced aggregation tendency renders recombinant and soluble production troublesome and complex. While prokaryotic expression systems can provide BMP2 in large amounts, the typically insoluble protein requires complex denaturation-renaturation procedures with medically hazardous reagents to obtain natively folded homodimeric BMP2. Based on a detailed aggregation analysis of wildtype BMP2, we designed a hydrophilic variant of BMP2 additionally containing an improved heparin binding site (BMP2-2Hep-7M). Consecutive optimization of BMP2-2Hep-7M expression and purification enabled production of soluble dimeric BMP2-2Hep-7M in high yield in E. coli. This was achieved by a) increasing protein hydrophilicity via introducing seven point mutations within aggregation hot spots of wildtype BMP2 and a longer N-terminus resulting in higher affinity for heparin, b) by employing E. coli strain SHuffle® T7, which enables the structurally essential disulfide-bond formation in BMP2 in the cytoplasm, c) by using BMP2 variant characteristic soluble expression conditions and application of l-arginine as solubility enhancer. The BMP2 variant BMP2-2Hep-7M shows strongly attenuated although not completely eliminated aggregation tendency.}, author = {Heinks, Tobias and Hettwer, Anette and Hiepen, Christian and Weise, Christoph and Gorka, Marcel and Knaus, Petra and Mueller, Thomas D. and Loidl-Stahlhofen, Angelika}, journal = {Protein Expression and Purification}, keywords = {myown}, pages = 105918, title = {Optimized expression and purification of a soluble BMP2 variant based on in-silico design}, volume = 186, year = 2021 }

  %0 Journal Article %1 HEINKS2021105918 %A Heinks, Tobias %A Hettwer, Anette %A Hiepen, Christian %A Weise, Christoph %A Gorka, Marcel %A Knaus, Petra %A Mueller, Thomas D. %A Loidl-Stahlhofen, Angelika %D 2021 %J Protein Expression and Purification %P 105918 %R https://doi.org/10.1016/j.pep.2021.105918 %T Optimized expression and purification of a soluble BMP2 variant based on in-silico design %U https://www.sciencedirect.com/science/article/pii/S1046592821001017 %V 186 %X Bone morphogenetic protein 2 (BMP21) is a highly interesting therapeutic growth factor due to its strong osteogenic/osteoinductive potential. However, its pronounced aggregation tendency renders recombinant and soluble production troublesome and complex. While prokaryotic expression systems can provide BMP2 in large amounts, the typically insoluble protein requires complex denaturation-renaturation procedures with medically hazardous reagents to obtain natively folded homodimeric BMP2. Based on a detailed aggregation analysis of wildtype BMP2, we designed a hydrophilic variant of BMP2 additionally containing an improved heparin binding site (BMP2-2Hep-7M). Consecutive optimization of BMP2-2Hep-7M expression and purification enabled production of soluble dimeric BMP2-2Hep-7M in high yield in E. coli. This was achieved by a) increasing protein hydrophilicity via introducing seven point mutations within aggregation hot spots of wildtype BMP2 and a longer N-terminus resulting in higher affinity for heparin, b) by employing E. coli strain SHuffle® T7, which enables the structurally essential disulfide-bond formation in BMP2 in the cytoplasm, c) by using BMP2 variant characteristic soluble expression conditions and application of l-arginine as solubility enhancer. The BMP2 variant BMP2-2Hep-7M shows strongly attenuated although not completely eliminated aggregation tendency.
• Imarazene, B., Du, K., Beille, S., Jouanno, E., Feron, R., Pan, Q., Torres-Paz, J., Lopez-Roques, C., Castinel, A., Gil, L., Kuchly, C., Donnadieu, C., Parrinello, H., Journot, L., Cabau, C., Zahm, M., Klopp, C., Pavlica, T., Al-Rikabi, A., Liehr, T., Simanovsky, S.A., Bohlen, J., Sember, A., Perez, J., Veyrunes, F., Mueller, T.D., Postlethwait, J.H., Schartl, M., Herpin, A., Rétaux, S., and Guiguen, Y. (2021) ‘A supernumerary “B-sex” chromosome drives male sex determination in the Pachón cavefish, Astyanax mexicanus’, Current Biology, 31(21), 4800–4809.e9, available: https://doi.org/https://doi.org/10.1016/j.cub.2021.08.030.
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  Summary Sex chromosomes are generally derived from a pair of classical type-A chromosomes, and relatively few alternative models have been proposed up to now.1,2 B chromosomes (Bs) are supernumerary and dispensable chromosomes with non-Mendelian inheritance found in many plant and animal species3,4 that have often been considered as selfish genetic elements that behave as genome parasites.5,6 The observation that in some species Bs can be either restricted or predominant in one sex7, 8, 9, 10, 11, 12, 13, 14 raised the interesting hypothesis that Bs could play a role in sex determination.15 The characterization of putative B master sex-determining (MSD) genes, however, has not yet been provided to support this hypothesis. Here, in Astyanax mexicanus cavefish originating from Pachón cave, we show that Bs are strongly male predominant. Based on a high-quality genome assembly of a B-carrying male, we characterized the Pachón cavefish B sequence and found that it contains two duplicated loci of the putative MSD gene growth differentiation factor 6b (gdf6b). Supporting its role as an MSD gene, we found that the Pachón cavefish gdf6b gene is expressed specifically in differentiating male gonads, and that its knockout induces male-to-female sex reversal in B-carrying males. This demonstrates that gdf6b is necessary for triggering male sex determination in Pachón cavefish. Altogether these results bring multiple and independent lines of evidence supporting the conclusion that the Pachón cavefish B is a “B-sex” chromosome that contains duplicated copies of the gdf6b gene, which can promote male sex determination in this species.

  @article{IMARAZENE20214800, abstract = {Summary Sex chromosomes are generally derived from a pair of classical type-A chromosomes, and relatively few alternative models have been proposed up to now.1,2 B chromosomes (Bs) are supernumerary and dispensable chromosomes with non-Mendelian inheritance found in many plant and animal species3,4 that have often been considered as selfish genetic elements that behave as genome parasites.5,6 The observation that in some species Bs can be either restricted or predominant in one sex7, 8, 9, 10, 11, 12, 13, 14 raised the interesting hypothesis that Bs could play a role in sex determination.15 The characterization of putative B master sex-determining (MSD) genes, however, has not yet been provided to support this hypothesis. Here, in Astyanax mexicanus cavefish originating from Pachón cave, we show that Bs are strongly male predominant. Based on a high-quality genome assembly of a B-carrying male, we characterized the Pachón cavefish B sequence and found that it contains two duplicated loci of the putative MSD gene growth differentiation factor 6b (gdf6b). Supporting its role as an MSD gene, we found that the Pachón cavefish gdf6b gene is expressed specifically in differentiating male gonads, and that its knockout induces male-to-female sex reversal in B-carrying males. This demonstrates that gdf6b is necessary for triggering male sex determination in Pachón cavefish. Altogether these results bring multiple and independent lines of evidence supporting the conclusion that the Pachón cavefish B is a “B-sex” chromosome that contains duplicated copies of the gdf6b gene, which can promote male sex determination in this species.}, author = {Imarazene, Boudjema and Du, Kang and Beille, Séverine and Jouanno, Elodie and Feron, Romain and Pan, Qiaowei and Torres-Paz, Jorge and Lopez-Roques, Céline and Castinel, Adrien and Gil, Lisa and Kuchly, Claire and Donnadieu, Cécile and Parrinello, Hugues and Journot, Laurent and Cabau, Cédric and Zahm, Margot and Klopp, Christophe and Pavlica, Tomáš and Al-Rikabi, Ahmed and Liehr, Thomas and Simanovsky, Sergey A. and Bohlen, Joerg and Sember, Alexandr and Perez, Julie and Veyrunes, Frédéric and Mueller, Thomas D. and Postlethwait, John H. and Schartl, Manfred and Herpin, Amaury and Rétaux, Sylvie and Guiguen, Yann}, journal = {Current Biology}, keywords = {myown}, number = 21, pages = {4800-4809.e9}, title = {A supernumerary “B-sex” chromosome drives male sex determination in the Pachón cavefish, Astyanax mexicanus}, volume = 31, year = 2021 }

  %0 Journal Article %1 IMARAZENE20214800 %A Imarazene, Boudjema %A Du, Kang %A Beille, Séverine %A Jouanno, Elodie %A Feron, Romain %A Pan, Qiaowei %A Torres-Paz, Jorge %A Lopez-Roques, Céline %A Castinel, Adrien %A Gil, Lisa %A Kuchly, Claire %A Donnadieu, Cécile %A Parrinello, Hugues %A Journot, Laurent %A Cabau, Cédric %A Zahm, Margot %A Klopp, Christophe %A Pavlica, Tomáš %A Al-Rikabi, Ahmed %A Liehr, Thomas %A Simanovsky, Sergey A. %A Bohlen, Joerg %A Sember, Alexandr %A Perez, Julie %A Veyrunes, Frédéric %A Mueller, Thomas D. %A Postlethwait, John H. %A Schartl, Manfred %A Herpin, Amaury %A Rétaux, Sylvie %A Guiguen, Yann %D 2021 %J Current Biology %N 21 %P 4800-4809.e9 %R https://doi.org/10.1016/j.cub.2021.08.030 %T A supernumerary “B-sex” chromosome drives male sex determination in the Pachón cavefish, Astyanax mexicanus %U https://www.sciencedirect.com/science/article/pii/S0960982221011349 %V 31 %X Summary Sex chromosomes are generally derived from a pair of classical type-A chromosomes, and relatively few alternative models have been proposed up to now.1,2 B chromosomes (Bs) are supernumerary and dispensable chromosomes with non-Mendelian inheritance found in many plant and animal species3,4 that have often been considered as selfish genetic elements that behave as genome parasites.5,6 The observation that in some species Bs can be either restricted or predominant in one sex7, 8, 9, 10, 11, 12, 13, 14 raised the interesting hypothesis that Bs could play a role in sex determination.15 The characterization of putative B master sex-determining (MSD) genes, however, has not yet been provided to support this hypothesis. Here, in Astyanax mexicanus cavefish originating from Pachón cave, we show that Bs are strongly male predominant. Based on a high-quality genome assembly of a B-carrying male, we characterized the Pachón cavefish B sequence and found that it contains two duplicated loci of the putative MSD gene growth differentiation factor 6b (gdf6b). Supporting its role as an MSD gene, we found that the Pachón cavefish gdf6b gene is expressed specifically in differentiating male gonads, and that its knockout induces male-to-female sex reversal in B-carrying males. This demonstrates that gdf6b is necessary for triggering male sex determination in Pachón cavefish. Altogether these results bring multiple and independent lines of evidence supporting the conclusion that the Pachón cavefish B is a “B-sex” chromosome that contains duplicated copies of the gdf6b gene, which can promote male sex determination in this species.
• Lehmann, J., Jørgensen, M.E., Fratz, S., Müller, H.M., Kusch, J., Scherzer, S., Navarro-Retamal, C., Mayer, D., Böhm, J., Konrad, K.R., Terpitz, U., Dreyer, I., Mueller, T.D., Sauer, M., Hedrich, R., Geiger, D., and Maierhofer, T. (2021) ‘Acidosis-induced activation of anion channel SLAH3 in the flooding-related stress response of Arabidopsis’, Current Biology, available: https://doi.org/https://doi.org/10.1016/j.cub.2021.06.018.
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  Summary Plants, as sessile organisms, gained the ability to sense and respond to biotic and abiotic stressors to survive severe changes in their environments. The change in our climate comes with extreme dry periods but also episodes of flooding. The latter stress condition causes anaerobiosis-triggered cytosolic acidosis and impairs plant function. The molecular mechanism that enables plant cells to sense acidity and convey this signal via membrane depolarization was previously unknown. Here, we show that acidosis-induced anion efflux from Arabidopsis (Arabidopsis thaliana) roots is dependent on the S-type anion channel AtSLAH3. Heterologous expression of SLAH3 in Xenopus oocytes revealed that the anion channel is directly activated by a small, physiological drop in cytosolic pH. Acidosis-triggered activation of SLAH3 is mediated by protonation of histidine 330 and 454. Super-resolution microscopy analysis showed that the increase in cellular proton concentration switches SLAH3 from an electrically silent channel dimer into its active monomeric form. Our results show that, upon acidification, protons directly switch SLAH3 to its open configuration, bypassing kinase-dependent activation. Moreover, under flooding conditions, the stress response of Arabidopsis wild-type (WT) plants was significantly higher compared to SLAH3 loss-of-function mutants. Our genetic evidence of SLAH3 pH sensor function may guide the development of crop varieties with improved stress tolerance.

  @article{LEHMANN2021, abstract = {Summary Plants, as sessile organisms, gained the ability to sense and respond to biotic and abiotic stressors to survive severe changes in their environments. The change in our climate comes with extreme dry periods but also episodes of flooding. The latter stress condition causes anaerobiosis-triggered cytosolic acidosis and impairs plant function. The molecular mechanism that enables plant cells to sense acidity and convey this signal via membrane depolarization was previously unknown. Here, we show that acidosis-induced anion efflux from Arabidopsis (Arabidopsis thaliana) roots is dependent on the S-type anion channel AtSLAH3. Heterologous expression of SLAH3 in Xenopus oocytes revealed that the anion channel is directly activated by a small, physiological drop in cytosolic pH. Acidosis-triggered activation of SLAH3 is mediated by protonation of histidine 330 and 454. Super-resolution microscopy analysis showed that the increase in cellular proton concentration switches SLAH3 from an electrically silent channel dimer into its active monomeric form. Our results show that, upon acidification, protons directly switch SLAH3 to its open configuration, bypassing kinase-dependent activation. Moreover, under flooding conditions, the stress response of Arabidopsis wild-type (WT) plants was significantly higher compared to SLAH3 loss-of-function mutants. Our genetic evidence of SLAH3 pH sensor function may guide the development of crop varieties with improved stress tolerance.}, author = {Lehmann, Julian and Jørgensen, Morten E. and Fratz, Stefanie and Müller, Heike M. and Kusch, Jana and Scherzer, Sönke and Navarro-Retamal, Carlos and Mayer, Dominik and Böhm, Jennifer and Konrad, Kai R. and Terpitz, Ulrich and Dreyer, Ingo and Mueller, Thomas D. and Sauer, Markus and Hedrich, Rainer and Geiger, Dietmar and Maierhofer, Tobias}, journal = {Current Biology}, keywords = {myown}, title = {Acidosis-induced activation of anion channel SLAH3 in the flooding-related stress response of Arabidopsis}, year = 2021 }

  %0 Journal Article %1 LEHMANN2021 %A Lehmann, Julian %A Jørgensen, Morten E. %A Fratz, Stefanie %A Müller, Heike M. %A Kusch, Jana %A Scherzer, Sönke %A Navarro-Retamal, Carlos %A Mayer, Dominik %A Böhm, Jennifer %A Konrad, Kai R. %A Terpitz, Ulrich %A Dreyer, Ingo %A Mueller, Thomas D. %A Sauer, Markus %A Hedrich, Rainer %A Geiger, Dietmar %A Maierhofer, Tobias %D 2021 %J Current Biology %R https://doi.org/10.1016/j.cub.2021.06.018 %T Acidosis-induced activation of anion channel SLAH3 in the flooding-related stress response of Arabidopsis %U https://www.sciencedirect.com/science/article/pii/S0960982221008137 %X Summary Plants, as sessile organisms, gained the ability to sense and respond to biotic and abiotic stressors to survive severe changes in their environments. The change in our climate comes with extreme dry periods but also episodes of flooding. The latter stress condition causes anaerobiosis-triggered cytosolic acidosis and impairs plant function. The molecular mechanism that enables plant cells to sense acidity and convey this signal via membrane depolarization was previously unknown. Here, we show that acidosis-induced anion efflux from Arabidopsis (Arabidopsis thaliana) roots is dependent on the S-type anion channel AtSLAH3. Heterologous expression of SLAH3 in Xenopus oocytes revealed that the anion channel is directly activated by a small, physiological drop in cytosolic pH. Acidosis-triggered activation of SLAH3 is mediated by protonation of histidine 330 and 454. Super-resolution microscopy analysis showed that the increase in cellular proton concentration switches SLAH3 from an electrically silent channel dimer into its active monomeric form. Our results show that, upon acidification, protons directly switch SLAH3 to its open configuration, bypassing kinase-dependent activation. Moreover, under flooding conditions, the stress response of Arabidopsis wild-type (WT) plants was significantly higher compared to SLAH3 loss-of-function mutants. Our genetic evidence of SLAH3 pH sensor function may guide the development of crop varieties with improved stress tolerance.

• Lauffer, P., Miranda-Laferte, E., van Duyvenvoorde, H.A., van Haeringen, A., Werner, F., Boudin, E., Schmidt, H., Mueller, T.D., Kuhn, M., and van der Kaay, D.C.M. (2020) ‘An Activating Deletion Variant in the Submembrane Region of Natriuretic Peptide Receptor-B Causes Tall Stature’, J Clin Endocrinol Metab, 105(7), available: https://doi.org/10.1210/clinem/dgaa190.
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  C-type natriuretic peptide (CNP) is critically involved in endochondral bone growth. Variants in the genes encoding CNP or its cyclic guanosine monophosphate (cGMP)-forming receptor (natriuretic peptide receptor-B [NPR-B], gene NPR2) cause monogenic growth disorders. Here we describe a novel gain-of-function variant of NPR-B associated with tall stature and macrodactyly of the great toes (epiphyseal chondrodysplasia, Miura type).History and clinical characteristics of 3 family members were collected. NPR2 was selected for sequencing. Skin fibroblasts and transfected HEK-293 cells were used to compare mutant versus wild-type NPR-B activities. Homology modeling was applied to understand the molecular consequences of the variant.Mother's height was +2.77 standard deviation scores (SDS). The heights of her 2 daughters were +1.96 SDS at 7 years and +1.30 SDS at 4 years of age. Skeletal surveys showed macrodactyly of the great toes and pseudo-epiphyses of the mid- and proximal phalanges. Sequencing identified a novel heterozygous variant c.1444_1449delATGCTG in exon 8 of NPR2, predicted to result in deletion of 2 amino acids Met482-Leu483 within the submembrane region of NPR-B. In proband's skin fibroblasts, basal cGMP levels and CNP-stimulated cGMP production were markedly increased compared with controls. Consistently, assays with transfected HEK-293 cells showed markedly augmented baseline and ligand-dependent activity of mutant NPR-B.We report the second activating variant within the intracellular submembrane region of NPR-B resulting in tall stature and macrodactyly. Our functional and modeling studies suggest that this domain plays a critical role in the baseline conformation and ligand-dependent structural rearrangement of NPR-B required for cGMP production.

  @article{Lauffer:2020:J-Clin-Endocrinol-Metab:32282051, abstract = {C-type natriuretic peptide (CNP) is critically involved in endochondral bone growth. Variants in the genes encoding CNP or its cyclic guanosine monophosphate (cGMP)-forming receptor (natriuretic peptide receptor-B [NPR-B], gene NPR2) cause monogenic growth disorders. Here we describe a novel gain-of-function variant of NPR-B associated with tall stature and macrodactyly of the great toes (epiphyseal chondrodysplasia, Miura type).History and clinical characteristics of 3 family members were collected. NPR2 was selected for sequencing. Skin fibroblasts and transfected HEK-293 cells were used to compare mutant versus wild-type NPR-B activities. Homology modeling was applied to understand the molecular consequences of the variant.Mother's height was +2.77 standard deviation scores (SDS). The heights of her 2 daughters were +1.96 SDS at 7 years and +1.30 SDS at 4 years of age. Skeletal surveys showed macrodactyly of the great toes and pseudo-epiphyses of the mid- and proximal phalanges. Sequencing identified a novel heterozygous variant c.1444\_1449delATGCTG in exon 8 of NPR2, predicted to result in deletion of 2 amino acids Met482-Leu483 within the submembrane region of NPR-B. In proband's skin fibroblasts, basal cGMP levels and CNP-stimulated cGMP production were markedly increased compared with controls. Consistently, assays with transfected HEK-293 cells showed markedly augmented baseline and ligand-dependent activity of mutant NPR-B.We report the second activating variant within the intracellular submembrane region of NPR-B resulting in tall stature and macrodactyly. Our functional and modeling studies suggest that this domain plays a critical role in the baseline conformation and ligand-dependent structural rearrangement of NPR-B required for cGMP production.}, author = {Lauffer, P and Miranda-Laferte, E and van Duyvenvoorde, H A and van Haeringen, A and Werner, F and Boudin, E and Schmidt, H and Mueller, T D and Kuhn, M and van der Kaay, D C M}, journal = {J Clin Endocrinol Metab}, keywords = {myown}, month = {07}, number = 7, title = {An Activating Deletion Variant in the Submembrane Region of Natriuretic Peptide Receptor-B Causes Tall Stature}, volume = 105, year = 2020 }

  %0 Journal Article %1 Lauffer:2020:J-Clin-Endocrinol-Metab:32282051 %A Lauffer, P %A Miranda-Laferte, E %A van Duyvenvoorde, H A %A van Haeringen, A %A Werner, F %A Boudin, E %A Schmidt, H %A Mueller, T D %A Kuhn, M %A van der Kaay, D C M %D 2020 %J J Clin Endocrinol Metab %N 7 %R 10.1210/clinem/dgaa190 %T An Activating Deletion Variant in the Submembrane Region of Natriuretic Peptide Receptor-B Causes Tall Stature %U https://pubmed.ncbi.nlm.nih.gov/32282051/ %V 105 %X C-type natriuretic peptide (CNP) is critically involved in endochondral bone growth. Variants in the genes encoding CNP or its cyclic guanosine monophosphate (cGMP)-forming receptor (natriuretic peptide receptor-B [NPR-B], gene NPR2) cause monogenic growth disorders. Here we describe a novel gain-of-function variant of NPR-B associated with tall stature and macrodactyly of the great toes (epiphyseal chondrodysplasia, Miura type).History and clinical characteristics of 3 family members were collected. NPR2 was selected for sequencing. Skin fibroblasts and transfected HEK-293 cells were used to compare mutant versus wild-type NPR-B activities. Homology modeling was applied to understand the molecular consequences of the variant.Mother's height was +2.77 standard deviation scores (SDS). The heights of her 2 daughters were +1.96 SDS at 7 years and +1.30 SDS at 4 years of age. Skeletal surveys showed macrodactyly of the great toes and pseudo-epiphyses of the mid- and proximal phalanges. Sequencing identified a novel heterozygous variant c.1444_1449delATGCTG in exon 8 of NPR2, predicted to result in deletion of 2 amino acids Met482-Leu483 within the submembrane region of NPR-B. In proband's skin fibroblasts, basal cGMP levels and CNP-stimulated cGMP production were markedly increased compared with controls. Consistently, assays with transfected HEK-293 cells showed markedly augmented baseline and ligand-dependent activity of mutant NPR-B.We report the second activating variant within the intracellular submembrane region of NPR-B resulting in tall stature and macrodactyly. Our functional and modeling studies suggest that this domain plays a critical role in the baseline conformation and ligand-dependent structural rearrangement of NPR-B required for cGMP production.
• Schinner, C., Erber, B.M., Yeruva, S., Schlipp, A., Rötzer, V., Kempf, E., Kant, S., Leube, R.E., Mueller, T.D., and Waschke, J. (2020) ‘Stabilization of desmoglein-2 binding rescues arrhythmia in arrhythmogenic cardiomyopathy’, {JCI} Insight, 5(9), available: https://doi.org/10.1172/jci.insight.130141.
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  @article{Schinner_2020, author = {Schinner, Camilla and Erber, Bernd Markus and Yeruva, Sunil and Schlipp, Angela and Rötzer, Vera and Kempf, Ellen and Kant, Sebastian and Leube, Rudolf E. and Mueller, Thomas D. and Waschke, Jens}, journal = {{JCI} Insight}, keywords = {myown}, month = {05}, number = 9, publisher = {American Society for Clinical Investigation}, title = {Stabilization of desmoglein-2 binding rescues arrhythmia in arrhythmogenic cardiomyopathy}, volume = 5, year = 2020 }

  %0 Journal Article %1 Schinner_2020 %A Schinner, Camilla %A Erber, Bernd Markus %A Yeruva, Sunil %A Schlipp, Angela %A Rötzer, Vera %A Kempf, Ellen %A Kant, Sebastian %A Leube, Rudolf E. %A Mueller, Thomas D. %A Waschke, Jens %D 2020 %I American Society for Clinical Investigation %J {JCI} Insight %N 9 %R 10.1172/jci.insight.130141 %T Stabilization of desmoglein-2 binding rescues arrhythmia in arrhythmogenic cardiomyopathy %U https://doi.org/10.1172%2Fjci.insight.130141 %V 5
• Malinauskas, T., Peer, T.V., Bishop, B., Mueller, T.D., and Siebold, C. (2020) ‘Repulsive guidance molecules lock growth differentiation factor 5 in an inhibitory complex’, Proceedins of the National Academy of Sciences of the United States of America, 117(27), 15620–15631, available: https://doi.org/https://doi.org/10.1073/pnas.2000561117.
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  Repulsive guidance molecules (RGMs) are cell surface proteins that regulate the development and homeostasis of many tissues and organs, including the nervous, skeletal, and immune systems. They control fundamental biological processes, such as migration and differentiation by direct interaction with the Neogenin (NEO1) receptor and function as coreceptors for the bone morphogenetic protein (BMP)/growth differentiation factor (GDF) family. We determined crystal structures of all three human RGM family members in complex with GDF5, as well as the ternary NEO1–RGMB–GDF5 assembly. Surprisingly, we show that all three RGMs inhibit GDF5 signaling, which is in stark contrast to RGM-mediated enhancement of signaling observed for other BMPs, like BMP2. Despite their opposite effect on GDF5 signaling, RGMs occupy the BMP type 1 receptor binding site similar to the observed interactions in RGM–BMP2 complexes. In the NEO1–RGMB–GDF5 complex, RGMB physically bridges NEO1 and GDF5, suggesting cross-talk between the GDF5 and NEO1 signaling pathways. Our crystal structures, combined with structure-guided mutagenesis of RGMs and BMP ligands, binding studies, and cellular assays suggest that RGMs inhibit GDF5 signaling by competing with GDF5 type 1 receptors. While our crystal structure analysis and in vitro binding data initially pointed towards a simple competition mechanism between RGMs and type 1 receptors as a possible basis for RGM-mediated GDF5 inhibition, further experiments utilizing BMP2-mimicking GDF5 variants clearly indicate a more complex mechanism that explains how RGMs can act as a functionality-changing switch for two structurally and biochemically similar signaling molecules.

  @article{noauthororeditor, abstract = {Repulsive guidance molecules (RGMs) are cell surface proteins that regulate the development and homeostasis of many tissues and organs, including the nervous, skeletal, and immune systems. They control fundamental biological processes, such as migration and differentiation by direct interaction with the Neogenin (NEO1) receptor and function as coreceptors for the bone morphogenetic protein (BMP)/growth differentiation factor (GDF) family. We determined crystal structures of all three human RGM family members in complex with GDF5, as well as the ternary NEO1–RGMB–GDF5 assembly. Surprisingly, we show that all three RGMs inhibit GDF5 signaling, which is in stark contrast to RGM-mediated enhancement of signaling observed for other BMPs, like BMP2. Despite their opposite effect on GDF5 signaling, RGMs occupy the BMP type 1 receptor binding site similar to the observed interactions in RGM–BMP2 complexes. In the NEO1–RGMB–GDF5 complex, RGMB physically bridges NEO1 and GDF5, suggesting cross-talk between the GDF5 and NEO1 signaling pathways. Our crystal structures, combined with structure-guided mutagenesis of RGMs and BMP ligands, binding studies, and cellular assays suggest that RGMs inhibit GDF5 signaling by competing with GDF5 type 1 receptors. While our crystal structure analysis and in vitro binding data initially pointed towards a simple competition mechanism between RGMs and type 1 receptors as a possible basis for RGM-mediated GDF5 inhibition, further experiments utilizing BMP2-mimicking GDF5 variants clearly indicate a more complex mechanism that explains how RGMs can act as a functionality-changing switch for two structurally and biochemically similar signaling molecules.}, author = {Malinauskas, Tomas and Peer, Tina Verena and Bishop, Benjamin and Mueller, Thomas Dieter and Siebold, Christian}, journal = {Proceedins of the National Academy of Sciences of the United States of America}, keywords = {myown}, number = 27, pages = {15620-15631}, title = {Repulsive guidance molecules lock growth differentiation factor 5 in an inhibitory complex}, volume = 117, year = 2020 }

  %0 Journal Article %1 noauthororeditor %A Malinauskas, Tomas %A Peer, Tina Verena %A Bishop, Benjamin %A Mueller, Thomas Dieter %A Siebold, Christian %D 2020 %J Proceedins of the National Academy of Sciences of the United States of America %N 27 %P 15620-15631 %R https://doi.org/10.1073/pnas.2000561117 %T Repulsive guidance molecules lock growth differentiation factor 5 in an inhibitory complex %U https://www.pnas.org/content/117/27/15620 %V 117 %X Repulsive guidance molecules (RGMs) are cell surface proteins that regulate the development and homeostasis of many tissues and organs, including the nervous, skeletal, and immune systems. They control fundamental biological processes, such as migration and differentiation by direct interaction with the Neogenin (NEO1) receptor and function as coreceptors for the bone morphogenetic protein (BMP)/growth differentiation factor (GDF) family. We determined crystal structures of all three human RGM family members in complex with GDF5, as well as the ternary NEO1–RGMB–GDF5 assembly. Surprisingly, we show that all three RGMs inhibit GDF5 signaling, which is in stark contrast to RGM-mediated enhancement of signaling observed for other BMPs, like BMP2. Despite their opposite effect on GDF5 signaling, RGMs occupy the BMP type 1 receptor binding site similar to the observed interactions in RGM–BMP2 complexes. In the NEO1–RGMB–GDF5 complex, RGMB physically bridges NEO1 and GDF5, suggesting cross-talk between the GDF5 and NEO1 signaling pathways. Our crystal structures, combined with structure-guided mutagenesis of RGMs and BMP ligands, binding studies, and cellular assays suggest that RGMs inhibit GDF5 signaling by competing with GDF5 type 1 receptors. While our crystal structure analysis and in vitro binding data initially pointed towards a simple competition mechanism between RGMs and type 1 receptors as a possible basis for RGM-mediated GDF5 inhibition, further experiments utilizing BMP2-mimicking GDF5 variants clearly indicate a more complex mechanism that explains how RGMs can act as a functionality-changing switch for two structurally and biochemically similar signaling molecules.

• Keller, T., Gorboulev, V., Mueller, T.D., D{ö}tsch, V., Bernhard, F., and Koepsell, H. (2019) ‘Rat Organic Cation Transporter 1 Contains Three Binding Sites for Substrate 1-Methyl-4-phenylpyridinium per Monomer’, Mol Pharmacol, 95(2), 169–182, available: https://doi.org/10.1124/mol.118.113498.
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  Organic cation transporters OCT1 (SLC22A1) and OCT2 (SLC22A2) are critically involved in absorption and excretion of diverse cationic drugs. Because drug-drug interactions at these transporters may induce adverse drug effects in patients, in vitro testing during drug development for interaction with the human transporters is mandatory. Recent data performed with rat OCT1 (rOCT1) suggest that currently performed in vitro tests assuming one polyspecific binding site are insufficient. Here we measured the binding and transport of model substrate 1-methyl-4-phenylpyridinium+ (MPP+) by cell-free-expressed fusion proteins of rOCT1 and rOCT1 mutants with green fluorescent protein that had been reconstituted into nanodiscs or proteoliposomes. The nanodiscs were formed with major scaffold protein (MSP) and different phospholipids, whereas the proteoliposomes were formed with a mixture of cholesterol, phosphatidylserine, and phosphatidylcholine. In nanodiscs formed with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine or cholesterol, phosphatidylserine, and phosphatidylcholine, two low-affinity MPP+ binding sites and one high-affinity MPP+ binding site per transporter monomer were determined. Mutagenesis revealed that tryptophan 218 and aspartate 475 in neighboring positions in the modeled outward-open cleft contribute to one low-affinity binding site, whereas arginine 440 located distantly in the cleft is critical for MPP+ binding to another low-affinity site. Comparing MPP+ binding with MPP+ transport suggests that the low-affinity sites are involved in MPP+ transport, whereas high-affinity MPP+ binding influences transport allosterically. The data will be helpful in the interpretation of future crystal structures and provides a rationale for future in vitro testing that is more sophisticated and reliable, leading to the generation of pharmacophore models with high predictive power.

  @article{Keller:2019:Mol-Pharmacol:30409791, abstract = {Organic cation transporters OCT1 (SLC22A1) and OCT2 (SLC22A2) are critically involved in absorption and excretion of diverse cationic drugs. Because drug-drug interactions at these transporters may induce adverse drug effects in patients, in vitro testing during drug development for interaction with the human transporters is mandatory. Recent data performed with rat OCT1 (rOCT1) suggest that currently performed in vitro tests assuming one polyspecific binding site are insufficient. Here we measured the binding and transport of model substrate 1-methyl-4-phenylpyridinium+ (MPP+) by cell-free-expressed fusion proteins of rOCT1 and rOCT1 mutants with green fluorescent protein that had been reconstituted into nanodiscs or proteoliposomes. The nanodiscs were formed with major scaffold protein (MSP) and different phospholipids, whereas the proteoliposomes were formed with a mixture of cholesterol, phosphatidylserine, and phosphatidylcholine. In nanodiscs formed with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine or cholesterol, phosphatidylserine, and phosphatidylcholine, two low-affinity MPP+ binding sites and one high-affinity MPP+ binding site per transporter monomer were determined. Mutagenesis revealed that tryptophan 218 and aspartate 475 in neighboring positions in the modeled outward-open cleft contribute to one low-affinity binding site, whereas arginine 440 located distantly in the cleft is critical for MPP+ binding to another low-affinity site. Comparing MPP+ binding with MPP+ transport suggests that the low-affinity sites are involved in MPP+ transport, whereas high-affinity MPP+ binding influences transport allosterically. The data will be helpful in the interpretation of future crystal structures and provides a rationale for future in vitro testing that is more sophisticated and reliable, leading to the generation of pharmacophore models with high predictive power.}, author = {Keller, T and Gorboulev, V and Mueller, T D and D{\"o}tsch, V and Bernhard, F and Koepsell, H}, journal = {Mol Pharmacol}, keywords = {myown}, month = {02}, number = 2, pages = {169-182}, title = {Rat Organic Cation Transporter 1 Contains Three Binding Sites for Substrate 1-Methyl-4-phenylpyridinium per Monomer}, volume = 95, year = 2019 }

  %0 Journal Article %1 Keller:2019:Mol-Pharmacol:30409791 %A Keller, T %A Gorboulev, V %A Mueller, T D %A D{ö}tsch, V %A Bernhard, F %A Koepsell, H %D 2019 %J Mol Pharmacol %N 2 %P 169-182 %R 10.1124/mol.118.113498 %T Rat Organic Cation Transporter 1 Contains Three Binding Sites for Substrate 1-Methyl-4-phenylpyridinium per Monomer %U https://www.ncbi.nlm.nih.gov/pubmed/30409791 %V 95 %X Organic cation transporters OCT1 (SLC22A1) and OCT2 (SLC22A2) are critically involved in absorption and excretion of diverse cationic drugs. Because drug-drug interactions at these transporters may induce adverse drug effects in patients, in vitro testing during drug development for interaction with the human transporters is mandatory. Recent data performed with rat OCT1 (rOCT1) suggest that currently performed in vitro tests assuming one polyspecific binding site are insufficient. Here we measured the binding and transport of model substrate 1-methyl-4-phenylpyridinium+ (MPP+) by cell-free-expressed fusion proteins of rOCT1 and rOCT1 mutants with green fluorescent protein that had been reconstituted into nanodiscs or proteoliposomes. The nanodiscs were formed with major scaffold protein (MSP) and different phospholipids, whereas the proteoliposomes were formed with a mixture of cholesterol, phosphatidylserine, and phosphatidylcholine. In nanodiscs formed with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine or cholesterol, phosphatidylserine, and phosphatidylcholine, two low-affinity MPP+ binding sites and one high-affinity MPP+ binding site per transporter monomer were determined. Mutagenesis revealed that tryptophan 218 and aspartate 475 in neighboring positions in the modeled outward-open cleft contribute to one low-affinity binding site, whereas arginine 440 located distantly in the cleft is critical for MPP+ binding to another low-affinity site. Comparing MPP+ binding with MPP+ transport suggests that the low-affinity sites are involved in MPP+ transport, whereas high-affinity MPP+ binding influences transport allosterically. The data will be helpful in the interpretation of future crystal structures and provides a rationale for future in vitro testing that is more sophisticated and reliable, leading to the generation of pharmacophore models with high predictive power.
• Nickel, J. and Mueller, T.D. (2019) ‘Specification of BMP Signaling’, Cells, 8(12), available: https://doi.org/10.3390/cells8121579.
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  Bone Morphogenetic Proteins (BMPs) together with the Growth and Differentiation Factors (GDFs) form the largest subgroup of the Transforming Growth Factor (TGF)β family and represent secreted growth factors, which play an essential role in many aspects of cell communication in higher organisms. As morphogens they exert crucial functions during embryonal development, but are also involved in tissue homeostasis and regeneration in the adult organism. Their involvement in maintenance and repair processes of various tissues and organs made these growth factors highly interesting targets for novel pharmaceutical applications in regenerative medicine. A hallmark of the TGFβ protein family is that all of the more than 30 growth factors identified to date signal by binding and hetero-oligomerization of a very limited set of transmembrane serine-threonine kinase receptors, which can be classified into two subgroups termed type I and type II. Only seven type I and five type II receptors exist for all 30plus TGFβ members suggesting a pronounced ligand-receptor promiscuity. Indeed, many TGFβ ligands can bind the same type I or type II receptor and a particular receptor of either subtype can usually interact with and bind various TGFβ ligands. The possible consequence of this ligand-receptor promiscuity is further aggravated by the finding that canonical TGFβ signaling of all family members seemingly results in the activation of just two distinct signaling pathways, that is either SMAD2/3 or SMAD1/5/8 activation. While this would implicate that different ligands can assemble seemingly identical receptor complexes that activate just either one of two distinct pathways, in vitro and in vivo analyses show that the different TGFβ members exert quite distinct biological functions with high specificity. This discrepancy indicates that our current view of TGFβ signaling initiation just by hetero-oligomerization of two receptor subtypes and transduction via two main pathways in an on-off switch manner is too simplified. Hence, the signals generated by the various TGFβ members are either quantitatively interpreted using the subtle differences in their receptor-binding properties leading to ligand-specific modulation of the downstream signaling cascade or additional components participating in the signaling activation complex allow diversification of the encoded signal in a ligand-dependent manner at all cellular levels. In this review we focus on signal specification of TGFβ members, particularly of BMPs and GDFs addressing the role of binding affinities, specificities, and kinetics of individual ligand-receptor interactions for the assembly of specific receptor complexes with potentially distinct signaling properties.

  @article{Nickel:2019:Cells:31817503, abstract = {Bone Morphogenetic Proteins (BMPs) together with the Growth and Differentiation Factors (GDFs) form the largest subgroup of the Transforming Growth Factor (TGF)β family and represent secreted growth factors, which play an essential role in many aspects of cell communication in higher organisms. As morphogens they exert crucial functions during embryonal development, but are also involved in tissue homeostasis and regeneration in the adult organism. Their involvement in maintenance and repair processes of various tissues and organs made these growth factors highly interesting targets for novel pharmaceutical applications in regenerative medicine. A hallmark of the TGFβ protein family is that all of the more than 30 growth factors identified to date signal by binding and hetero-oligomerization of a very limited set of transmembrane serine-threonine kinase receptors, which can be classified into two subgroups termed type I and type II. Only seven type I and five type II receptors exist for all 30plus TGFβ members suggesting a pronounced ligand-receptor promiscuity. Indeed, many TGFβ ligands can bind the same type I or type II receptor and a particular receptor of either subtype can usually interact with and bind various TGFβ ligands. The possible consequence of this ligand-receptor promiscuity is further aggravated by the finding that canonical TGFβ signaling of all family members seemingly results in the activation of just two distinct signaling pathways, that is either SMAD2/3 or SMAD1/5/8 activation. While this would implicate that different ligands can assemble seemingly identical receptor complexes that activate just either one of two distinct pathways, in vitro and in vivo analyses show that the different TGFβ members exert quite distinct biological functions with high specificity. This discrepancy indicates that our current view of TGFβ signaling initiation just by hetero-oligomerization of two receptor subtypes and transduction via two main pathways in an on-off switch manner is too simplified. Hence, the signals generated by the various TGFβ members are either quantitatively interpreted using the subtle differences in their receptor-binding properties leading to ligand-specific modulation of the downstream signaling cascade or additional components participating in the signaling activation complex allow diversification of the encoded signal in a ligand-dependent manner at all cellular levels. In this review we focus on signal specification of TGFβ members, particularly of BMPs and GDFs addressing the role of binding affinities, specificities, and kinetics of individual ligand-receptor interactions for the assembly of specific receptor complexes with potentially distinct signaling properties.}, author = {Nickel, J and Mueller, T D}, journal = {Cells}, keywords = {BMPs}, month = 12, number = 12, title = {Specification of BMP Signaling}, volume = 8, year = 2019 }

  %0 Journal Article %1 Nickel:2019:Cells:31817503 %A Nickel, J %A Mueller, T D %D 2019 %J Cells %N 12 %R 10.3390/cells8121579 %T Specification of BMP Signaling %U https://www.ncbi.nlm.nih.gov/pubmed/31817503 %V 8 %X Bone Morphogenetic Proteins (BMPs) together with the Growth and Differentiation Factors (GDFs) form the largest subgroup of the Transforming Growth Factor (TGF)β family and represent secreted growth factors, which play an essential role in many aspects of cell communication in higher organisms. As morphogens they exert crucial functions during embryonal development, but are also involved in tissue homeostasis and regeneration in the adult organism. Their involvement in maintenance and repair processes of various tissues and organs made these growth factors highly interesting targets for novel pharmaceutical applications in regenerative medicine. A hallmark of the TGFβ protein family is that all of the more than 30 growth factors identified to date signal by binding and hetero-oligomerization of a very limited set of transmembrane serine-threonine kinase receptors, which can be classified into two subgroups termed type I and type II. Only seven type I and five type II receptors exist for all 30plus TGFβ members suggesting a pronounced ligand-receptor promiscuity. Indeed, many TGFβ ligands can bind the same type I or type II receptor and a particular receptor of either subtype can usually interact with and bind various TGFβ ligands. The possible consequence of this ligand-receptor promiscuity is further aggravated by the finding that canonical TGFβ signaling of all family members seemingly results in the activation of just two distinct signaling pathways, that is either SMAD2/3 or SMAD1/5/8 activation. While this would implicate that different ligands can assemble seemingly identical receptor complexes that activate just either one of two distinct pathways, in vitro and in vivo analyses show that the different TGFβ members exert quite distinct biological functions with high specificity. This discrepancy indicates that our current view of TGFβ signaling initiation just by hetero-oligomerization of two receptor subtypes and transduction via two main pathways in an on-off switch manner is too simplified. Hence, the signals generated by the various TGFβ members are either quantitatively interpreted using the subtle differences in their receptor-binding properties leading to ligand-specific modulation of the downstream signaling cascade or additional components participating in the signaling activation complex allow diversification of the encoded signal in a ligand-dependent manner at all cellular levels. In this review we focus on signal specification of TGFβ members, particularly of BMPs and GDFs addressing the role of binding affinities, specificities, and kinetics of individual ligand-receptor interactions for the assembly of specific receptor complexes with potentially distinct signaling properties.
• Scheide-Noeth, J.P., Rosen, M., Baumstark, D., Dietz, H., and Mueller, T.D. (2019) ‘Structural Basis of Interleukin-5 Inhibition by the Small Cyclic Peptide AF17121’, J Mol Biol, 431(4), 714–731, available: https://doi.org/10.1016/j.jmb.2018.11.029.
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  Interleukin-5 (IL-5) is a T-helper cell of subtype 2 cytokine involved in many aspects of eosinophil life. Eosinophilic granulocytes play a pathogenic role in the progression of atopic diseases, such as allergy, asthma and atopic dermatitis and hypereosinophilic syndromes. Here, eosinophils upon activation degranulate leading to the release of proinflammatory proteins and mediators stored in intracellular vesicles termed granula thereby causing local inflammation, which when persisting leads to tissue damage and organ failure. As a key regulator of eosinophil function, IL-5 therefore presents a major pharmaceutical target and approaches to interfere with IL-5 receptor activation are of great interest. Here we present the structure of the IL-5 inhibiting peptide AF17121 bound to the extracellular domain of the IL-5 receptor IL-5Rα. The small 18mer cyclic peptide snugly fits into the wrench-like cleft of the IL-5 receptor, thereby blocking access of key residues for IL-5 binding. While AF17121 and IL-5 seemingly bind to a similar epitope at IL-5Rα, functional studies show that recognition and binding of both ligands differ. Using the structure data, peptide variants with improved IL-5 inhibition have been generated, which might present valuable starting points for superior peptide-based IL-5 antagonists.

  @article{ScheideNoeth:2019:J-Mol-Biol:30529748, abstract = {Interleukin-5 (IL-5) is a T-helper cell of subtype 2 cytokine involved in many aspects of eosinophil life. Eosinophilic granulocytes play a pathogenic role in the progression of atopic diseases, such as allergy, asthma and atopic dermatitis and hypereosinophilic syndromes. Here, eosinophils upon activation degranulate leading to the release of proinflammatory proteins and mediators stored in intracellular vesicles termed granula thereby causing local inflammation, which when persisting leads to tissue damage and organ failure. As a key regulator of eosinophil function, IL-5 therefore presents a major pharmaceutical target and approaches to interfere with IL-5 receptor activation are of great interest. Here we present the structure of the IL-5 inhibiting peptide AF17121 bound to the extracellular domain of the IL-5 receptor IL-5Rα. The small 18mer cyclic peptide snugly fits into the wrench-like cleft of the IL-5 receptor, thereby blocking access of key residues for IL-5 binding. While AF17121 and IL-5 seemingly bind to a similar epitope at IL-5Rα, functional studies show that recognition and binding of both ligands differ. Using the structure data, peptide variants with improved IL-5 inhibition have been generated, which might present valuable starting points for superior peptide-based IL-5 antagonists.}, author = {Scheide-Noeth, J P and Rosen, M and Baumstark, D and Dietz, H and Mueller, T D}, journal = {J Mol Biol}, keywords = {myown}, month = {02}, number = 4, pages = {714-731}, title = {Structural Basis of Interleukin-5 Inhibition by the Small Cyclic Peptide AF17121}, volume = 431, year = 2019 }

  %0 Journal Article %1 ScheideNoeth:2019:J-Mol-Biol:30529748 %A Scheide-Noeth, J P %A Rosen, M %A Baumstark, D %A Dietz, H %A Mueller, T D %D 2019 %J J Mol Biol %N 4 %P 714-731 %R 10.1016/j.jmb.2018.11.029 %T Structural Basis of Interleukin-5 Inhibition by the Small Cyclic Peptide AF17121 %U https://www.ncbi.nlm.nih.gov/pubmed/30529748 %V 431 %X Interleukin-5 (IL-5) is a T-helper cell of subtype 2 cytokine involved in many aspects of eosinophil life. Eosinophilic granulocytes play a pathogenic role in the progression of atopic diseases, such as allergy, asthma and atopic dermatitis and hypereosinophilic syndromes. Here, eosinophils upon activation degranulate leading to the release of proinflammatory proteins and mediators stored in intracellular vesicles termed granula thereby causing local inflammation, which when persisting leads to tissue damage and organ failure. As a key regulator of eosinophil function, IL-5 therefore presents a major pharmaceutical target and approaches to interfere with IL-5 receptor activation are of great interest. Here we present the structure of the IL-5 inhibiting peptide AF17121 bound to the extracellular domain of the IL-5 receptor IL-5Rα. The small 18mer cyclic peptide snugly fits into the wrench-like cleft of the IL-5 receptor, thereby blocking access of key residues for IL-5 binding. While AF17121 and IL-5 seemingly bind to a similar epitope at IL-5Rα, functional studies show that recognition and binding of both ligands differ. Using the structure data, peptide variants with improved IL-5 inhibition have been generated, which might present valuable starting points for superior peptide-based IL-5 antagonists.
• Vissing, J., Johnson, K., T{ö}pf, A., Nafissi, S., D{í}az-Manera, J., French, V.M., Schindler, R.F., Sarathchandra, P., Lokken, N., Rinn{é}, S., Freund, M., Decher, N., M{ü}ller, T., Duno, M., Krag, T., Brand, T., and Straub, V. (2019) ‘POPDC3 Gene Variants Associate with a New Form of Limb Girdle Muscular Dystrophy’, Ann Neurol, 86(6), 832–843, available: https://doi.org/10.1002/ana.25620.
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  The Popeye domain containing 3 (POPDC3) gene encodes a membrane protein involved in cyclic adenosine monophosphate (cAMP) signaling. Besides gastric cancer, no disease association has been described. We describe a new muscular dystrophy associated with this gene.We screened 1,500 patients with unclassified limb girdle weakness or hyperCKemia for pathogenic POPDC3 variants. Five patients carrying POPDC3 variants were examined by muscle magnetic resonance imaging (MRI), muscle biopsy, and cardiac examination. We performed functional analyses in a zebrafish popdc3 knockdown model and heterologous expression of the mutant proteins in Xenopus laevis oocytes to measure TREK-1 current.We identified homozygous POPDC3 missense variants (p.Leu155His, p.Leu217Phe, and p.Arg261Gln) in 5 patients from 3 ethnically distinct families. Variants affected highly conserved residues in the Popeye (p.Leu155 and p.Leu217) and carboxy-terminal (p.Arg261) domains. The variants were almost absent from control populations. Probands' muscle biopsies were dystrophic, and serum creatine kinase levels were 1,050 to 9,200U/l. Muscle weakness was proximal with adulthood onset in most patients and affected lower earlier than upper limbs. Muscle MRI revealed fat replacement of paraspinal and proximal leg muscles; cardiac investigations were unremarkable. Knockdown of popdc3 in zebrafish, using 2 different splice-site blocking morpholinos, resulted in larvae with tail curling and dystrophic muscle features. All 3 mutants cloned in Xenopus oocytes caused an aberrant modulation of the mechano-gated potassium channel, TREK-1.Our findings point to an important role of POPDC3 for skeletal muscle function and suggest that pathogenic variants in POPDC3 are responsible for a novel type of autosomal recessive limb girdle muscular dystrophy. ANN NEUROL 2019;86:832-843.

  @article{Vissing:2019:Ann-Neurol:31610034, abstract = {The Popeye domain containing 3 (POPDC3) gene encodes a membrane protein involved in cyclic adenosine monophosphate (cAMP) signaling. Besides gastric cancer, no disease association has been described. We describe a new muscular dystrophy associated with this gene.We screened 1,500 patients with unclassified limb girdle weakness or hyperCKemia for pathogenic POPDC3 variants. Five patients carrying POPDC3 variants were examined by muscle magnetic resonance imaging (MRI), muscle biopsy, and cardiac examination. We performed functional analyses in a zebrafish popdc3 knockdown model and heterologous expression of the mutant proteins in Xenopus laevis oocytes to measure TREK-1 current.We identified homozygous POPDC3 missense variants (p.Leu155His, p.Leu217Phe, and p.Arg261Gln) in 5 patients from 3 ethnically distinct families. Variants affected highly conserved residues in the Popeye (p.Leu155 and p.Leu217) and carboxy-terminal (p.Arg261) domains. The variants were almost absent from control populations. Probands' muscle biopsies were dystrophic, and serum creatine kinase levels were 1,050 to 9,200U/l. Muscle weakness was proximal with adulthood onset in most patients and affected lower earlier than upper limbs. Muscle MRI revealed fat replacement of paraspinal and proximal leg muscles; cardiac investigations were unremarkable. Knockdown of popdc3 in zebrafish, using 2 different splice-site blocking morpholinos, resulted in larvae with tail curling and dystrophic muscle features. All 3 mutants cloned in Xenopus oocytes caused an aberrant modulation of the mechano-gated potassium channel, TREK-1.Our findings point to an important role of POPDC3 for skeletal muscle function and suggest that pathogenic variants in POPDC3 are responsible for a novel type of autosomal recessive limb girdle muscular dystrophy. ANN NEUROL 2019;86:832-843.}, author = {Vissing, J and Johnson, K and T{\"o}pf, A and Nafissi, S and D{\'i}az-Manera, J and French, V M and Schindler, R F and Sarathchandra, P and Lokken, N and Rinn{\'e}, S and Freund, M and Decher, N and M{\"u}ller, T and Duno, M and Krag, T and Brand, T and Straub, V}, journal = {Ann Neurol}, keywords = {own}, month = 12, number = 6, pages = {832-843}, title = {POPDC3 Gene Variants Associate with a New Form of Limb Girdle Muscular Dystrophy}, volume = 86, year = 2019 }

  %0 Journal Article %1 Vissing:2019:Ann-Neurol:31610034 %A Vissing, J %A Johnson, K %A T{ö}pf, A %A Nafissi, S %A D{í}az-Manera, J %A French, V M %A Schindler, R F %A Sarathchandra, P %A Lokken, N %A Rinn{é}, S %A Freund, M %A Decher, N %A M{ü}ller, T %A Duno, M %A Krag, T %A Brand, T %A Straub, V %D 2019 %J Ann Neurol %N 6 %P 832-843 %R 10.1002/ana.25620 %T POPDC3 Gene Variants Associate with a New Form of Limb Girdle Muscular Dystrophy %U https://www.ncbi.nlm.nih.gov/pubmed/31610034 %V 86 %X The Popeye domain containing 3 (POPDC3) gene encodes a membrane protein involved in cyclic adenosine monophosphate (cAMP) signaling. Besides gastric cancer, no disease association has been described. We describe a new muscular dystrophy associated with this gene.We screened 1,500 patients with unclassified limb girdle weakness or hyperCKemia for pathogenic POPDC3 variants. Five patients carrying POPDC3 variants were examined by muscle magnetic resonance imaging (MRI), muscle biopsy, and cardiac examination. We performed functional analyses in a zebrafish popdc3 knockdown model and heterologous expression of the mutant proteins in Xenopus laevis oocytes to measure TREK-1 current.We identified homozygous POPDC3 missense variants (p.Leu155His, p.Leu217Phe, and p.Arg261Gln) in 5 patients from 3 ethnically distinct families. Variants affected highly conserved residues in the Popeye (p.Leu155 and p.Leu217) and carboxy-terminal (p.Arg261) domains. The variants were almost absent from control populations. Probands' muscle biopsies were dystrophic, and serum creatine kinase levels were 1,050 to 9,200U/l. Muscle weakness was proximal with adulthood onset in most patients and affected lower earlier than upper limbs. Muscle MRI revealed fat replacement of paraspinal and proximal leg muscles; cardiac investigations were unremarkable. Knockdown of popdc3 in zebrafish, using 2 different splice-site blocking morpholinos, resulted in larvae with tail curling and dystrophic muscle features. All 3 mutants cloned in Xenopus oocytes caused an aberrant modulation of the mechano-gated potassium channel, TREK-1.Our findings point to an important role of POPDC3 for skeletal muscle function and suggest that pathogenic variants in POPDC3 are responsible for a novel type of autosomal recessive limb girdle muscular dystrophy. ANN NEUROL 2019;86:832-843.

• Bertho, S., Herpin, A., Branthonne, A., Jouanno, E., Yano, A., Nicol, B., Muller, T., Pannetier, M., Pailhoux, E., Miwa, M., Yoshizaki, G., Schartl, M., and Guiguen, Y. (2018) ‘The unusual rainbow trout sex determination gene hijacked the canonical vertebrate gonadal differentiation pathway’, Proc Natl Acad Sci U S A, available: https://doi.org/10.1073/pnas.1803826115.
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  Evolutionary novelties require rewiring of transcriptional networks and/or the evolution of new gene functions. Sex determination (SD), one of the most plastic evolutionary processes, requires such novelties. Studies on the evolution of vertebrate SD revealed that new master SD genes are generally recruited from genes involved in the downstream SD regulatory genetic network. Only a single exception to this rule is currently known in vertebrates: the intriguing case of the salmonid master SD gene (sdY), which arose from duplication of an immune-related gene. This exception immediately posed the question of how a gene outside from the classical sex differentiation cascade could acquire its function as a male SD gene. Here we show that SdY became integrated in the classical vertebrate sex differentiation cascade by interacting with the Forkhead box domain of the female-determining transcription factor, Foxl2. In the presence of Foxl2, SdY is translocated to the nucleus where the SdY:Foxl2 complex prevents activation of the aromatase (cyp19a1a) promoter in cooperation with Nr5a1 (Sf1). Hence, by blocking a positive loop of regulation needed for the synthesis of estrogens in the early differentiating gonad, SdY disrupts a preset female differentiation pathway, consequently allowing testicular differentiation to proceed. These results also suggest that the evolution of unusual vertebrate master sex determination genes recruited from outside the classical pathway like sdY is strongly constrained by their ability to interact with the canonical gonadal differentiation pathway.

  @article{Bertho:2018:Proc-Natl-Acad-Sci-U-S-A:30463951, abstract = {Evolutionary novelties require rewiring of transcriptional networks and/or the evolution of new gene functions. Sex determination (SD), one of the most plastic evolutionary processes, requires such novelties. Studies on the evolution of vertebrate SD revealed that new master SD genes are generally recruited from genes involved in the downstream SD regulatory genetic network. Only a single exception to this rule is currently known in vertebrates: the intriguing case of the salmonid master SD gene (sdY), which arose from duplication of an immune-related gene. This exception immediately posed the question of how a gene outside from the classical sex differentiation cascade could acquire its function as a male SD gene. Here we show that SdY became integrated in the classical vertebrate sex differentiation cascade by interacting with the Forkhead box domain of the female-determining transcription factor, Foxl2. In the presence of Foxl2, SdY is translocated to the nucleus where the SdY:Foxl2 complex prevents activation of the aromatase (cyp19a1a) promoter in cooperation with Nr5a1 (Sf1). Hence, by blocking a positive loop of regulation needed for the synthesis of estrogens in the early differentiating gonad, SdY disrupts a preset female differentiation pathway, consequently allowing testicular differentiation to proceed. These results also suggest that the evolution of unusual vertebrate master sex determination genes recruited from outside the classical pathway like sdY is strongly constrained by their ability to interact with the canonical gonadal differentiation pathway.}, author = {Bertho, S and Herpin, A and Branthonne, A and Jouanno, E and Yano, A and Nicol, B and Muller, T and Pannetier, M and Pailhoux, E and Miwa, M and Yoshizaki, G and Schartl, M and Guiguen, Y}, journal = {Proc Natl Acad Sci U S A}, keywords = {own}, month = 11, title = {The unusual rainbow trout sex determination gene hijacked the canonical vertebrate gonadal differentiation pathway}, year = 2018 }

  %0 Journal Article %1 Bertho:2018:Proc-Natl-Acad-Sci-U-S-A:30463951 %A Bertho, S %A Herpin, A %A Branthonne, A %A Jouanno, E %A Yano, A %A Nicol, B %A Muller, T %A Pannetier, M %A Pailhoux, E %A Miwa, M %A Yoshizaki, G %A Schartl, M %A Guiguen, Y %D 2018 %J Proc Natl Acad Sci U S A %R 10.1073/pnas.1803826115 %T The unusual rainbow trout sex determination gene hijacked the canonical vertebrate gonadal differentiation pathway %U https://www.ncbi.nlm.nih.gov/pubmed/30463951 %X Evolutionary novelties require rewiring of transcriptional networks and/or the evolution of new gene functions. Sex determination (SD), one of the most plastic evolutionary processes, requires such novelties. Studies on the evolution of vertebrate SD revealed that new master SD genes are generally recruited from genes involved in the downstream SD regulatory genetic network. Only a single exception to this rule is currently known in vertebrates: the intriguing case of the salmonid master SD gene (sdY), which arose from duplication of an immune-related gene. This exception immediately posed the question of how a gene outside from the classical sex differentiation cascade could acquire its function as a male SD gene. Here we show that SdY became integrated in the classical vertebrate sex differentiation cascade by interacting with the Forkhead box domain of the female-determining transcription factor, Foxl2. In the presence of Foxl2, SdY is translocated to the nucleus where the SdY:Foxl2 complex prevents activation of the aromatase (cyp19a1a) promoter in cooperation with Nr5a1 (Sf1). Hence, by blocking a positive loop of regulation needed for the synthesis of estrogens in the early differentiating gonad, SdY disrupts a preset female differentiation pathway, consequently allowing testicular differentiation to proceed. These results also suggest that the evolution of unusual vertebrate master sex determination genes recruited from outside the classical pathway like sdY is strongly constrained by their ability to interact with the canonical gonadal differentiation pathway.
• Braun, A.C., Gutmann, M., Mueller, T.D., L{ü}hmann, T., and Meinel, L. (2018) ‘Bioresponsive release of insulin-like growth factor-I from its PEGylated conjugate’, J Control Release, 279, 17–28, available: https://doi.org/10.1016/j.jconrel.2018.04.009.
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  PEGylation of protein ligands, the attachment of polyethylene glycol (PEG) polymers to a therapeutic protein, increases therapeutics' half-life but frequently comes at the cost of reduced bioactivity. We are now presenting a bioinspired strategy leading out of this dilemma. To this end, we selected a position within insulin-like growth factor I (IGF-I) for decoration with a PEG30kDa-modified protease-sensitive peptide linker (PSL) using a combination of enzymatic and chemical bioorthogonal coupling strategies. The PSL sequence responded to matrix metalloproteinases (MMP) to provide a targeted release in diseased tissue. The IGF-PSL-PEG conjugate had different binding protein affinity, cell proliferation, and endocytosis patterns as compared to the wild type. Exposure of the conjugate to elevated levels of activated MMPs, as present in inflamed tissues, fully reestablished the wild type properties through effective PSL cleavage. In conclusion, this bioinspired approach provided a blueprint for PEGylated therapeutics combining the pharmacokinetic advantages of PEGylation, while locally restoring the full suite of biological potential of therapeutics.

  @article{Braun:2018:J-Control-Release:29634992, abstract = {PEGylation of protein ligands, the attachment of polyethylene glycol (PEG) polymers to a therapeutic protein, increases therapeutics' half-life but frequently comes at the cost of reduced bioactivity. We are now presenting a bioinspired strategy leading out of this dilemma. To this end, we selected a position within insulin-like growth factor I (IGF-I) for decoration with a PEG30kDa-modified protease-sensitive peptide linker (PSL) using a combination of enzymatic and chemical bioorthogonal coupling strategies. The PSL sequence responded to matrix metalloproteinases (MMP) to provide a targeted release in diseased tissue. The IGF-PSL-PEG conjugate had different binding protein affinity, cell proliferation, and endocytosis patterns as compared to the wild type. Exposure of the conjugate to elevated levels of activated MMPs, as present in inflamed tissues, fully reestablished the wild type properties through effective PSL cleavage. In conclusion, this bioinspired approach provided a blueprint for PEGylated therapeutics combining the pharmacokinetic advantages of PEGylation, while locally restoring the full suite of biological potential of therapeutics.}, author = {Braun, A C and Gutmann, M and Mueller, T D and L{\"u}hmann, T and Meinel, L}, journal = {J Control Release}, keywords = {myown}, month = {04}, pages = {17-28}, title = {Bioresponsive release of insulin-like growth factor-I from its PEGylated conjugate}, volume = 279, year = 2018 }

  %0 Journal Article %1 Braun:2018:J-Control-Release:29634992 %A Braun, A C %A Gutmann, M %A Mueller, T D %A L{ü}hmann, T %A Meinel, L %D 2018 %J J Control Release %P 17-28 %R 10.1016/j.jconrel.2018.04.009 %T Bioresponsive release of insulin-like growth factor-I from its PEGylated conjugate %U https://www.ncbi.nlm.nih.gov/pubmed/29634992 %V 279 %X PEGylation of protein ligands, the attachment of polyethylene glycol (PEG) polymers to a therapeutic protein, increases therapeutics' half-life but frequently comes at the cost of reduced bioactivity. We are now presenting a bioinspired strategy leading out of this dilemma. To this end, we selected a position within insulin-like growth factor I (IGF-I) for decoration with a PEG30kDa-modified protease-sensitive peptide linker (PSL) using a combination of enzymatic and chemical bioorthogonal coupling strategies. The PSL sequence responded to matrix metalloproteinases (MMP) to provide a targeted release in diseased tissue. The IGF-PSL-PEG conjugate had different binding protein affinity, cell proliferation, and endocytosis patterns as compared to the wild type. Exposure of the conjugate to elevated levels of activated MMPs, as present in inflamed tissues, fully reestablished the wild type properties through effective PSL cleavage. In conclusion, this bioinspired approach provided a blueprint for PEGylated therapeutics combining the pharmacokinetic advantages of PEGylation, while locally restoring the full suite of biological potential of therapeutics.
• Hedrich, R., Mueller, T.D., Becker, D., and Marten, I. (2018) ‘Structure and Function of TPC1 Vacuole SV Channel Gains Shape’, Mol Plant, available: https://doi.org/10.1016/j.molp.2018.03.017.
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  Plants and animals in endosomes operate TPC1/SV-type cation channels. Although all plant cells functionally express at least one TPC1 gene, and the encoded SV channel was already discovered in the plant vacuole membrane two decades ago, its biological function has remained enigmatic. Recently, the structure of a plant TPC1/SV channel protein was determined. Insights into the 3D topology has now guided site-directed mutation approaches, enabling SV channel structure-function analyses and shed new light on earlier findings. Fou2 plants operating a hyperactive mutant form of TPC1 develop wounding stress phenotypes. Recent studies with fou2 and mutants that lack functional TPC1 have revealed atypical features in local and long-distance stress signaling, providing new access to the previously mysterious biology of this vacuolar cation channel type in planta.

  @article{Hedrich:2018:Mol-Plant:29614320, abstract = {Plants and animals in endosomes operate TPC1/SV-type cation channels. Although all plant cells functionally express at least one TPC1 gene, and the encoded SV channel was already discovered in the plant vacuole membrane two decades ago, its biological function has remained enigmatic. Recently, the structure of a plant TPC1/SV channel protein was determined. Insights into the 3D topology has now guided site-directed mutation approaches, enabling SV channel structure-function analyses and shed new light on earlier findings. Fou2 plants operating a hyperactive mutant form of TPC1 develop wounding stress phenotypes. Recent studies with fou2 and mutants that lack functional TPC1 have revealed atypical features in local and long-distance stress signaling, providing new access to the previously mysterious biology of this vacuolar cation channel type in planta.}, author = {Hedrich, R and Mueller, T D and Becker, D and Marten, I}, journal = {Mol Plant}, keywords = {myown}, month = {03}, title = {Structure and Function of TPC1 Vacuole SV Channel Gains Shape}, year = 2018 }

  %0 Journal Article %1 Hedrich:2018:Mol-Plant:29614320 %A Hedrich, R %A Mueller, T D %A Becker, D %A Marten, I %D 2018 %J Mol Plant %R 10.1016/j.molp.2018.03.017 %T Structure and Function of TPC1 Vacuole SV Channel Gains Shape %U https://www.ncbi.nlm.nih.gov/pubmed/29614320 %X Plants and animals in endosomes operate TPC1/SV-type cation channels. Although all plant cells functionally express at least one TPC1 gene, and the encoded SV channel was already discovered in the plant vacuole membrane two decades ago, its biological function has remained enigmatic. Recently, the structure of a plant TPC1/SV channel protein was determined. Insights into the 3D topology has now guided site-directed mutation approaches, enabling SV channel structure-function analyses and shed new light on earlier findings. Fou2 plants operating a hyperactive mutant form of TPC1 develop wounding stress phenotypes. Recent studies with fou2 and mutants that lack functional TPC1 have revealed atypical features in local and long-distance stress signaling, providing new access to the previously mysterious biology of this vacuolar cation channel type in planta.
• Siverino, C., Tabisz, B., L{ü}hmann, T., Meinel, L., M{ü}ller, T., Walles, H., and Nickel, J. (2018) ‘Site-Directed Immobilization of Bone Morphogenetic Protein 2 to Solid Surfaces by Click Chemistry’, J Vis Exp, (133), available: https://doi.org/10.3791/56616.
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  Different therapeutic strategies for the treatment of non-healing long bone defects have been intensively investigated. Currently used treatments present several limitations that have led to the use of biomaterials in combination with osteogenic growth factors, such as bone morphogenetic proteins (BMPs). Commonly used absorption or encapsulation methods require supra-physiological amounts of BMP2, typically resulting in a so-called initial burst release effect that provokes several severe adverse side effects. A possible strategy to overcome these problems would be to covalently couple the protein to the scaffold. Moreover, coupling should be performed in a site-specific manner in order to guarantee a reproducible product outcome. Therefore, we created a BMP2 variant, in which an artificial amino acid (propargyl-L-lysine) was introduced into the mature part of the BMP2 protein by codon usage expansion (BMP2-K3Plk). BMP2-K3Plk was coupled to functionalized beads through copper catalyzed azide-alkyne cycloaddition (CuAAC). The biological activity of the coupled BMP2-K3Plk was proven in vitro and the osteogenic activity of the BMP2-K3Plk-functionalized beads was proven in cell based assays. The functionalized beads in contact with C2C12 cells were able to induce alkaline phosphatase (ALP) expression in locally restricted proximity of the bead. Thus, by this technique, functionalized scaffolds can be produced that can trigger cell differentiation towards an osteogenic lineage. Additionally, lower BMP2 doses are sufficient due to the controlled orientation of site-directed coupled BMP2. With this method, BMPs are always exposed to their receptors on the cell surface in the appropriate orientation, which is not the case if the factors are coupled via non-site-directed coupling techniques. The product outcome is highly controllable and, thus, results in materials with homogeneous properties, improving their applicability for the repair of critical size bone defects.

  @article{Siverino:2018:J-Vis-Exp:29658921, abstract = {Different therapeutic strategies for the treatment of non-healing long bone defects have been intensively investigated. Currently used treatments present several limitations that have led to the use of biomaterials in combination with osteogenic growth factors, such as bone morphogenetic proteins (BMPs). Commonly used absorption or encapsulation methods require supra-physiological amounts of BMP2, typically resulting in a so-called initial burst release effect that provokes several severe adverse side effects. A possible strategy to overcome these problems would be to covalently couple the protein to the scaffold. Moreover, coupling should be performed in a site-specific manner in order to guarantee a reproducible product outcome. Therefore, we created a BMP2 variant, in which an artificial amino acid (propargyl-L-lysine) was introduced into the mature part of the BMP2 protein by codon usage expansion (BMP2-K3Plk). BMP2-K3Plk was coupled to functionalized beads through copper catalyzed azide-alkyne cycloaddition (CuAAC). The biological activity of the coupled BMP2-K3Plk was proven in vitro and the osteogenic activity of the BMP2-K3Plk-functionalized beads was proven in cell based assays. The functionalized beads in contact with C2C12 cells were able to induce alkaline phosphatase (ALP) expression in locally restricted proximity of the bead. Thus, by this technique, functionalized scaffolds can be produced that can trigger cell differentiation towards an osteogenic lineage. Additionally, lower BMP2 doses are sufficient due to the controlled orientation of site-directed coupled BMP2. With this method, BMPs are always exposed to their receptors on the cell surface in the appropriate orientation, which is not the case if the factors are coupled via non-site-directed coupling techniques. The product outcome is highly controllable and, thus, results in materials with homogeneous properties, improving their applicability for the repair of critical size bone defects.}, author = {Siverino, C and Tabisz, B and L{\"u}hmann, T and Meinel, L and M{\"u}ller, T and Walles, H and Nickel, J}, journal = {J Vis Exp}, keywords = {myown}, month = {03}, number = 133, title = {Site-Directed Immobilization of Bone Morphogenetic Protein 2 to Solid Surfaces by Click Chemistry}, year = 2018 }

  %0 Journal Article %1 Siverino:2018:J-Vis-Exp:29658921 %A Siverino, C %A Tabisz, B %A L{ü}hmann, T %A Meinel, L %A M{ü}ller, T %A Walles, H %A Nickel, J %D 2018 %J J Vis Exp %N 133 %R 10.3791/56616 %T Site-Directed Immobilization of Bone Morphogenetic Protein 2 to Solid Surfaces by Click Chemistry %U https://www.ncbi.nlm.nih.gov/pubmed/29658921 %X Different therapeutic strategies for the treatment of non-healing long bone defects have been intensively investigated. Currently used treatments present several limitations that have led to the use of biomaterials in combination with osteogenic growth factors, such as bone morphogenetic proteins (BMPs). Commonly used absorption or encapsulation methods require supra-physiological amounts of BMP2, typically resulting in a so-called initial burst release effect that provokes several severe adverse side effects. A possible strategy to overcome these problems would be to covalently couple the protein to the scaffold. Moreover, coupling should be performed in a site-specific manner in order to guarantee a reproducible product outcome. Therefore, we created a BMP2 variant, in which an artificial amino acid (propargyl-L-lysine) was introduced into the mature part of the BMP2 protein by codon usage expansion (BMP2-K3Plk). BMP2-K3Plk was coupled to functionalized beads through copper catalyzed azide-alkyne cycloaddition (CuAAC). The biological activity of the coupled BMP2-K3Plk was proven in vitro and the osteogenic activity of the BMP2-K3Plk-functionalized beads was proven in cell based assays. The functionalized beads in contact with C2C12 cells were able to induce alkaline phosphatase (ALP) expression in locally restricted proximity of the bead. Thus, by this technique, functionalized scaffolds can be produced that can trigger cell differentiation towards an osteogenic lineage. Additionally, lower BMP2 doses are sufficient due to the controlled orientation of site-directed coupled BMP2. With this method, BMPs are always exposed to their receptors on the cell surface in the appropriate orientation, which is not the case if the factors are coupled via non-site-directed coupling techniques. The product outcome is highly controllable and, thus, results in materials with homogeneous properties, improving their applicability for the repair of critical size bone defects.
• Mumcuoglu, D., de Miguel, L., Jekhmane, S., Siverino, C., Nickel, J., Mueller, T.D., van Leeuwen, J.P., van Osch, G.J., and Kluijtmans, S.G. (2018) ‘Collagen I derived recombinant protein microspheres as novel delivery vehicles for bone morphogenetic protein-2’, Mater Sci Eng C Mater Biol Appl, 84, 271–280, available: https://doi.org/10.1016/j.msec.2017.11.031.
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  Bone morphogenetic protein-2 (BMP-2) is a powerful osteoinductive protein; however, there is a need for the development of a safe and efficient BMP-2 release system for bone regeneration therapies. Recombinant extracellular matrix proteins are promising next generation biomaterials since the proteins are well-defined, reproducible and can be tailored for specific applications. In this study, we have developed a novel and versatile BMP-2 delivery system using microspheres from a recombinant protein based on human collagen I (RCP). In general, a two-phase release pattern was observed while the majority of BMP-2 was retained in the microspheres for at least two weeks. Among different parameters studied, the crosslinking and the size of the RCP microspheres changed the in vitro BMP-2 release kinetics significantly. Increasing the chemical crosslinking (hexamethylene diisocyanide) degree decreased the amount of initial burst release (24h) from 23% to 17%. Crosslinking by dehydrothermal treatment further decreased the burst release to 11%. Interestingly, the 50 and 72μm-sized spheres showed a significant decrease in the burst release compared to 207-μm sized spheres. Very importantly, using a reporter cell line, the released BMP-2 was shown to be bioactive. SPR data showed that N-terminal sequence of BMP-2 was important for the binding and retention of BMP-2 and suggested the presence of a specific binding epitope on RCP (KD: 1.2nM). This study demonstrated that the presented RCP microspheres are promising versatile BMP-2 delivery vehicles.

  @article{Mumcuoglu:2018:Mater-Sci-Eng-C-Mater-Biol-Appl:29519439, abstract = {Bone morphogenetic protein-2 (BMP-2) is a powerful osteoinductive protein; however, there is a need for the development of a safe and efficient BMP-2 release system for bone regeneration therapies. Recombinant extracellular matrix proteins are promising next generation biomaterials since the proteins are well-defined, reproducible and can be tailored for specific applications. In this study, we have developed a novel and versatile BMP-2 delivery system using microspheres from a recombinant protein based on human collagen I (RCP). In general, a two-phase release pattern was observed while the majority of BMP-2 was retained in the microspheres for at least two weeks. Among different parameters studied, the crosslinking and the size of the RCP microspheres changed the in vitro BMP-2 release kinetics significantly. Increasing the chemical crosslinking (hexamethylene diisocyanide) degree decreased the amount of initial burst release (24h) from 23% to 17%. Crosslinking by dehydrothermal treatment further decreased the burst release to 11%. Interestingly, the 50 and 72μm-sized spheres showed a significant decrease in the burst release compared to 207-μm sized spheres. Very importantly, using a reporter cell line, the released BMP-2 was shown to be bioactive. SPR data showed that N-terminal sequence of BMP-2 was important for the binding and retention of BMP-2 and suggested the presence of a specific binding epitope on RCP (KD: 1.2nM). This study demonstrated that the presented RCP microspheres are promising versatile BMP-2 delivery vehicles.}, author = {Mumcuoglu, D and de Miguel, L and Jekhmane, S and Siverino, C and Nickel, J and Mueller, T D and van Leeuwen, J P and van Osch, G J and Kluijtmans, S G}, journal = {Mater Sci Eng C Mater Biol Appl}, keywords = {myown}, month = {03}, pages = {271-280}, title = {Collagen I derived recombinant protein microspheres as novel delivery vehicles for bone morphogenetic protein-2}, volume = 84, year = 2018 }

  %0 Journal Article %1 Mumcuoglu:2018:Mater-Sci-Eng-C-Mater-Biol-Appl:29519439 %A Mumcuoglu, D %A de Miguel, L %A Jekhmane, S %A Siverino, C %A Nickel, J %A Mueller, T D %A van Leeuwen, J P %A van Osch, G J %A Kluijtmans, S G %D 2018 %J Mater Sci Eng C Mater Biol Appl %P 271-280 %R 10.1016/j.msec.2017.11.031 %T Collagen I derived recombinant protein microspheres as novel delivery vehicles for bone morphogenetic protein-2 %U https://www.ncbi.nlm.nih.gov/pubmed/29519439 %V 84 %X Bone morphogenetic protein-2 (BMP-2) is a powerful osteoinductive protein; however, there is a need for the development of a safe and efficient BMP-2 release system for bone regeneration therapies. Recombinant extracellular matrix proteins are promising next generation biomaterials since the proteins are well-defined, reproducible and can be tailored for specific applications. In this study, we have developed a novel and versatile BMP-2 delivery system using microspheres from a recombinant protein based on human collagen I (RCP). In general, a two-phase release pattern was observed while the majority of BMP-2 was retained in the microspheres for at least two weeks. Among different parameters studied, the crosslinking and the size of the RCP microspheres changed the in vitro BMP-2 release kinetics significantly. Increasing the chemical crosslinking (hexamethylene diisocyanide) degree decreased the amount of initial burst release (24h) from 23% to 17%. Crosslinking by dehydrothermal treatment further decreased the burst release to 11%. Interestingly, the 50 and 72μm-sized spheres showed a significant decrease in the burst release compared to 207-μm sized spheres. Very importantly, using a reporter cell line, the released BMP-2 was shown to be bioactive. SPR data showed that N-terminal sequence of BMP-2 was important for the binding and retention of BMP-2 and suggested the presence of a specific binding epitope on RCP (KD: 1.2nM). This study demonstrated that the presented RCP microspheres are promising versatile BMP-2 delivery vehicles.
• Gorboulev, V., Rehman, S., Albert, C.M., Roth, U., Meyer, M.J., Tzvetkov, M.V., Mueller, T.D., and Koepsell, H. (2018) ‘Assay Conditions Influence Affinities of Rat Organic Cation Transporter 1: Analysis of Mutagenesis in the Modeled Outward-facing Cleft by Measuring Effects of Substrates and Inhibitors on Initial Uptake’, Mol Pharmacol, available: https://doi.org/10.1124/mol.117.110767.
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  Effects of mutations in the modeled outward-open cleft of rat organic cation transporter 1 (rOCT1) on affinities of substrates and inhibitors were investigated. Human embryonic kidney (HEK) 293 cells were stably transfected with rOCT1 or rOCT1 mutants, and uptake of the substrates 1-methyl-4-phenylpyridinium+ (MPP+) and tetraethylammonium+ (TEA+) or inhibition of MPP+ uptake by the non-transported inhibitors tetrabutylammonium+ (TBuA+), tetrapentylammonium+ (TPeA+) and corticosterone was measured. Uptake measurements were performed on confluent cell layers using 2 min-incubation or in dissociated cells using incubation times of 1, 5, or 10 s. With both methods different apparent Michaelis-Menten Km values, different half-maximal inhibitor concentrations (IC50), and varying effects of mutations were determined. In addition, varying IC50 values for inhibition of MPP+ uptake and varying effects of mutations were obtained when different MPP+ concentrations far below the apparent Km value were used for uptake measurements. Eleven mutations were investigated by measuring initial uptake in dissociated cells and employing 0.1 μM MPP+ for uptake during inhibition experiments. Altered affinities for substrates and/or inhibitors were observed when Phe160, Trp218, Arg440, Leu447 and Asp475 were mutated. The mutations resulted in changes of apparent Km values for TEA+ and/or MPP+ Mutation of Trp218 and Asp475 led to altered IC50 values for TBuA+, TPeA+ and corticosterone, whereas mutation of Phe160 and Leu447 changed the IC50 values for two inhibitors. Thereby amino acids in the outward-facing conformation of rOCT1 could be identified that interact with structurally different inhibitors and probably also with different substrates.

  @article{Gorboulev:2018:Mol-Pharmacol:29339398, abstract = {Effects of mutations in the modeled outward-open cleft of rat organic cation transporter 1 (rOCT1) on affinities of substrates and inhibitors were investigated. Human embryonic kidney (HEK) 293 cells were stably transfected with rOCT1 or rOCT1 mutants, and uptake of the substrates 1-methyl-4-phenylpyridinium+ (MPP+) and tetraethylammonium+ (TEA+) or inhibition of MPP+ uptake by the non-transported inhibitors tetrabutylammonium+ (TBuA+), tetrapentylammonium+ (TPeA+) and corticosterone was measured. Uptake measurements were performed on confluent cell layers using 2 min-incubation or in dissociated cells using incubation times of 1, 5, or 10 s. With both methods different apparent Michaelis-Menten Km values, different half-maximal inhibitor concentrations (IC50), and varying effects of mutations were determined. In addition, varying IC50 values for inhibition of MPP+ uptake and varying effects of mutations were obtained when different MPP+ concentrations far below the apparent Km value were used for uptake measurements. Eleven mutations were investigated by measuring initial uptake in dissociated cells and employing 0.1 μM MPP+ for uptake during inhibition experiments. Altered affinities for substrates and/or inhibitors were observed when Phe160, Trp218, Arg440, Leu447 and Asp475 were mutated. The mutations resulted in changes of apparent Km values for TEA+ and/or MPP+ Mutation of Trp218 and Asp475 led to altered IC50 values for TBuA+, TPeA+ and corticosterone, whereas mutation of Phe160 and Leu447 changed the IC50 values for two inhibitors. Thereby amino acids in the outward-facing conformation of rOCT1 could be identified that interact with structurally different inhibitors and probably also with different substrates.}, author = {Gorboulev, V and Rehman, S and Albert, C M and Roth, U and Meyer, M J and Tzvetkov, M V and Mueller, T D and Koepsell, H}, journal = {Mol Pharmacol}, keywords = {myown}, month = {01}, title = {Assay Conditions Influence Affinities of Rat Organic Cation Transporter 1: Analysis of Mutagenesis in the Modeled Outward-facing Cleft by Measuring Effects of Substrates and Inhibitors on Initial Uptake}, year = 2018 }

  %0 Journal Article %1 Gorboulev:2018:Mol-Pharmacol:29339398 %A Gorboulev, V %A Rehman, S %A Albert, C M %A Roth, U %A Meyer, M J %A Tzvetkov, M V %A Mueller, T D %A Koepsell, H %D 2018 %J Mol Pharmacol %R 10.1124/mol.117.110767 %T Assay Conditions Influence Affinities of Rat Organic Cation Transporter 1: Analysis of Mutagenesis in the Modeled Outward-facing Cleft by Measuring Effects of Substrates and Inhibitors on Initial Uptake %U https://www.ncbi.nlm.nih.gov/pubmed/29339398 %X Effects of mutations in the modeled outward-open cleft of rat organic cation transporter 1 (rOCT1) on affinities of substrates and inhibitors were investigated. Human embryonic kidney (HEK) 293 cells were stably transfected with rOCT1 or rOCT1 mutants, and uptake of the substrates 1-methyl-4-phenylpyridinium+ (MPP+) and tetraethylammonium+ (TEA+) or inhibition of MPP+ uptake by the non-transported inhibitors tetrabutylammonium+ (TBuA+), tetrapentylammonium+ (TPeA+) and corticosterone was measured. Uptake measurements were performed on confluent cell layers using 2 min-incubation or in dissociated cells using incubation times of 1, 5, or 10 s. With both methods different apparent Michaelis-Menten Km values, different half-maximal inhibitor concentrations (IC50), and varying effects of mutations were determined. In addition, varying IC50 values for inhibition of MPP+ uptake and varying effects of mutations were obtained when different MPP+ concentrations far below the apparent Km value were used for uptake measurements. Eleven mutations were investigated by measuring initial uptake in dissociated cells and employing 0.1 μM MPP+ for uptake during inhibition experiments. Altered affinities for substrates and/or inhibitors were observed when Phe160, Trp218, Arg440, Leu447 and Asp475 were mutated. The mutations resulted in changes of apparent Km values for TEA+ and/or MPP+ Mutation of Trp218 and Asp475 led to altered IC50 values for TBuA+, TPeA+ and corticosterone, whereas mutation of Phe160 and Leu447 changed the IC50 values for two inhibitors. Thereby amino acids in the outward-facing conformation of rOCT1 could be identified that interact with structurally different inhibitors and probably also with different substrates.
• Nickel, J., Ten Dijke, P., and Mueller, T.D. (2018) ‘TGF-β family co-receptor function and signaling’, Acta Biochim Biophys Sin (Shanghai), 50(1), 12–36, available: https://doi.org/10.1093/abbs/gmx126.
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  Transforming growth factor-β (TGF-β) family members, which include TGF-βs, activins and bone morphogenetic proteins, are pleiotropic cytokines that elicit cell type-specific effects in a highly context-dependent manner in many different tissues. These secreted protein ligands signal via single-transmembrane Type I and Type II serine/threonine kinase receptors and intracellular SMAD transcription factors. Deregulation in signaling has been implicated in a broad array of diseases, and implicate the need for intricate fine tuning in cellular signaling responses. One important emerging mechanism by which TGF-β family receptor signaling intensity, duration, specificity and diversity are regulated and/or mediated is through cell surface co-receptors. Here, we provide an overview of the co-receptors that have been identified for TGF-β family members. While some appear to be specific to TGF-β family members, others are shared with other pathways and provide possible ways for signal integration. This review focuses on novel functions of TGF-β family co-receptors, which continue to be discovered.

  @article{Nickel:2018:Acta-Biochim-Biophys-Sin-Shanghai:29293886, abstract = {Transforming growth factor-β (TGF-β) family members, which include TGF-βs, activins and bone morphogenetic proteins, are pleiotropic cytokines that elicit cell type-specific effects in a highly context-dependent manner in many different tissues. These secreted protein ligands signal via single-transmembrane Type I and Type II serine/threonine kinase receptors and intracellular SMAD transcription factors. Deregulation in signaling has been implicated in a broad array of diseases, and implicate the need for intricate fine tuning in cellular signaling responses. One important emerging mechanism by which TGF-β family receptor signaling intensity, duration, specificity and diversity are regulated and/or mediated is through cell surface co-receptors. Here, we provide an overview of the co-receptors that have been identified for TGF-β family members. While some appear to be specific to TGF-β family members, others are shared with other pathways and provide possible ways for signal integration. This review focuses on novel functions of TGF-β family co-receptors, which continue to be discovered.}, author = {Nickel, J and Ten Dijke, P and Mueller, T D}, journal = {Acta Biochim Biophys Sin (Shanghai)}, keywords = {myown}, month = {01}, number = 1, pages = {12-36}, title = {TGF-β family co-receptor function and signaling}, volume = 50, year = 2018 }

  %0 Journal Article %1 Nickel:2018:Acta-Biochim-Biophys-Sin-Shanghai:29293886 %A Nickel, J %A Ten Dijke, P %A Mueller, T D %D 2018 %J Acta Biochim Biophys Sin (Shanghai) %N 1 %P 12-36 %R 10.1093/abbs/gmx126 %T TGF-β family co-receptor function and signaling %U https://www.ncbi.nlm.nih.gov/pubmed/29293886 %V 50 %X Transforming growth factor-β (TGF-β) family members, which include TGF-βs, activins and bone morphogenetic proteins, are pleiotropic cytokines that elicit cell type-specific effects in a highly context-dependent manner in many different tissues. These secreted protein ligands signal via single-transmembrane Type I and Type II serine/threonine kinase receptors and intracellular SMAD transcription factors. Deregulation in signaling has been implicated in a broad array of diseases, and implicate the need for intricate fine tuning in cellular signaling responses. One important emerging mechanism by which TGF-β family receptor signaling intensity, duration, specificity and diversity are regulated and/or mediated is through cell surface co-receptors. Here, we provide an overview of the co-receptors that have been identified for TGF-β family members. While some appear to be specific to TGF-β family members, others are shared with other pathways and provide possible ways for signal integration. This review focuses on novel functions of TGF-β family co-receptors, which continue to be discovered.

• Lagler, C., El-Mesery, M., K{ü}bler, A.C., M{ü}ller-Richter, U.D.A., St{ü}hmer, T., Nickel, J., M{ü}ller, T.D., Wajant, H., and Seher, A. (2017) ‘The anti-myeloma activity of bone morphogenetic protein 2 predominantly relies on the induction of growth arrest and is apoptosis-independent’, PLoS One, 12(10), available: https://doi.org/10.1371/journal.pone.0185720.
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  Multiple myeloma (MM), a malignancy of the bone marrow, is characterized by a pathological increase in antibody-producing plasma cells and an increase in immunoglobulins (plasmacytosis). In recent years, bone morphogenetic proteins (BMPs) have been reported to be activators of apoptotic cell death in neoplastic B cells in MM. Here, we use bone morphogenetic protein 2 (BMP2) to show that the "apoptotic" effect of BMPs on human neoplastic B cells is dominated by anti-proliferative activities and cell cycle arrest and is apoptosis-independent. The anti-proliferative effect of BMP2 was analysed in the human cell lines KMS12-BM and L363 using WST-1 and a Coulter counter and was confirmed using CytoTox assays with established inhibitors of programmed cell death (zVAD-fmk and necrostatin-1). Furthermore, apoptotic activity was compared in both cell lines employing western blot analysis for caspase 3 and 8 in cells treated with BMP2 and FasL. Additionally, expression profiles of marker genes of different cell death pathways were analysed in both cell lines after stimulation with BMP2 for 48h using an RT-PCR-based array. In our experiments we observed that there was rather no reduction in absolute cell number, but cells stopped proliferating following treatment with BMP2 instead. The time frame (48-72 h) after BMP2 treatment at which a reduction in cell number is detectable is too long to indicate a directly BMP2-triggered apoptosis. Moreover, in comparison to robust apoptosis induced by the approved apoptotic factor FasL, BMP2 only marginally induced cell death. Consistently, neither the known inhibitor of apoptotic cell death zVAD-fmk nor the necroptosis inhibitor necrostatin-1 was able to rescue myeloma cell growth in the presence of BMP2.

  @article{Lagler:2017:PLoS-One:29028819, abstract = {Multiple myeloma (MM), a malignancy of the bone marrow, is characterized by a pathological increase in antibody-producing plasma cells and an increase in immunoglobulins (plasmacytosis). In recent years, bone morphogenetic proteins (BMPs) have been reported to be activators of apoptotic cell death in neoplastic B cells in MM. Here, we use bone morphogenetic protein 2 (BMP2) to show that the "apoptotic" effect of BMPs on human neoplastic B cells is dominated by anti-proliferative activities and cell cycle arrest and is apoptosis-independent. The anti-proliferative effect of BMP2 was analysed in the human cell lines KMS12-BM and L363 using WST-1 and a Coulter counter and was confirmed using CytoTox assays with established inhibitors of programmed cell death (zVAD-fmk and necrostatin-1). Furthermore, apoptotic activity was compared in both cell lines employing western blot analysis for caspase 3 and 8 in cells treated with BMP2 and FasL. Additionally, expression profiles of marker genes of different cell death pathways were analysed in both cell lines after stimulation with BMP2 for 48h using an RT-PCR-based array. In our experiments we observed that there was rather no reduction in absolute cell number, but cells stopped proliferating following treatment with BMP2 instead. The time frame (48-72 h) after BMP2 treatment at which a reduction in cell number is detectable is too long to indicate a directly BMP2-triggered apoptosis. Moreover, in comparison to robust apoptosis induced by the approved apoptotic factor FasL, BMP2 only marginally induced cell death. Consistently, neither the known inhibitor of apoptotic cell death zVAD-fmk nor the necroptosis inhibitor necrostatin-1 was able to rescue myeloma cell growth in the presence of BMP2.}, author = {Lagler, C and El-Mesery, M and K{\"u}bler, A C and M{\"u}ller-Richter, U D A and St{\"u}hmer, T and Nickel, J and M{\"u}ller, T D and Wajant, H and Seher, A}, journal = {PLoS One}, keywords = {myown}, number = 10, title = {The anti-myeloma activity of bone morphogenetic protein 2 predominantly relies on the induction of growth arrest and is apoptosis-independent}, volume = 12, year = 2017 }

  %0 Journal Article %1 Lagler:2017:PLoS-One:29028819 %A Lagler, C %A El-Mesery, M %A K{ü}bler, A C %A M{ü}ller-Richter, U D A %A St{ü}hmer, T %A Nickel, J %A M{ü}ller, T D %A Wajant, H %A Seher, A %D 2017 %J PLoS One %N 10 %R 10.1371/journal.pone.0185720 %T The anti-myeloma activity of bone morphogenetic protein 2 predominantly relies on the induction of growth arrest and is apoptosis-independent %U https://www.ncbi.nlm.nih.gov/pubmed/29028819 %V 12 %X Multiple myeloma (MM), a malignancy of the bone marrow, is characterized by a pathological increase in antibody-producing plasma cells and an increase in immunoglobulins (plasmacytosis). In recent years, bone morphogenetic proteins (BMPs) have been reported to be activators of apoptotic cell death in neoplastic B cells in MM. Here, we use bone morphogenetic protein 2 (BMP2) to show that the "apoptotic" effect of BMPs on human neoplastic B cells is dominated by anti-proliferative activities and cell cycle arrest and is apoptosis-independent. The anti-proliferative effect of BMP2 was analysed in the human cell lines KMS12-BM and L363 using WST-1 and a Coulter counter and was confirmed using CytoTox assays with established inhibitors of programmed cell death (zVAD-fmk and necrostatin-1). Furthermore, apoptotic activity was compared in both cell lines employing western blot analysis for caspase 3 and 8 in cells treated with BMP2 and FasL. Additionally, expression profiles of marker genes of different cell death pathways were analysed in both cell lines after stimulation with BMP2 for 48h using an RT-PCR-based array. In our experiments we observed that there was rather no reduction in absolute cell number, but cells stopped proliferating following treatment with BMP2 instead. The time frame (48-72 h) after BMP2 treatment at which a reduction in cell number is detectable is too long to indicate a directly BMP2-triggered apoptosis. Moreover, in comparison to robust apoptosis induced by the approved apoptotic factor FasL, BMP2 only marginally induced cell death. Consistently, neither the known inhibitor of apoptotic cell death zVAD-fmk nor the necroptosis inhibitor necrostatin-1 was able to rescue myeloma cell growth in the presence of BMP2.
• Patino, L., Walton, K.L., Mueller, T., Johnson, K.E., Stocker, W., Richani, D., Agapiou, D., Gilchrist, R.B., Laissue, P., and Harrison, C.A. (2017) ‘BMP15 Mutations Associated With Primary Ovarian Insufficiency Reduce Expression, Activity, or Synergy With GDF9’, J Clin Endocrinol Metab, 102(3), 1009–1019.
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  @article{patino2017bmp15, author = {Patino, L.C. and Walton, K. L. and Mueller, T.D. and Johnson, K. E. and Stocker, W. and Richani, D. and Agapiou, D. and Gilchrist, R. B. and Laissue, P. and Harrison, C. A.}, journal = {J Clin Endocrinol Metab}, keywords = {imported}, number = 3, pages = {1009-1019}, title = {BMP15 Mutations Associated With Primary Ovarian Insufficiency Reduce Expression, Activity, or Synergy With GDF9}, type = {Journal Article}, volume = 102, year = 2017 }

  %0 Journal Article %1 patino2017bmp15 %A Patino, L.C. %A Walton, K. L. %A Mueller, T.D. %A Johnson, K. E. %A Stocker, W. %A Richani, D. %A Agapiou, D. %A Gilchrist, R. B. %A Laissue, P. %A Harrison, C. A. %D 2017 %J J Clin Endocrinol Metab %N 3 %P 1009-1019 %T BMP15 Mutations Associated With Primary Ovarian Insufficiency Reduce Expression, Activity, or Synergy With GDF9 %V 102
• Silva-Vilches, C., Pletinckx, K., Lohnert, M., Pavlovic, V., Ashour, D., John, V., Vendelova, E., Kneitz, S., Zhou, J., Chen, R., Reinheckel, T., Mueller, T.D., Bodem, J., and Lutz, M.B. (2017) ‘Low doses of cholera toxin and its mediator cAMP induce CTLA-2 secretion by dendritic cells to enhance regulatory T cell conversion’, PLoS One, 12(7), available: https://doi.org/10.1371/journal.pone.0178114.
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  Immature or semi-mature dendritic cells (DCs) represent tolerogenic maturation stages that can convert naive T cells into Foxp3+ induced regulatory T cells (iTreg). Here we found that murine bone marrow-derived DCs (BM-DCs) treated with cholera toxin (CT) matured by up-regulating MHC-II and costimulatory molecules using either high or low doses of CT (CThi, CTlo) or with cAMP, a known mediator CT signals. However, all three conditions also induced mRNA of both isoforms of the tolerogenic molecule cytotoxic T lymphocyte antigen 2 (CTLA-2α and CTLA-2β). Only DCs matured under CThi conditions secreted IL-1β, IL-6 and IL-23 leading to the instruction of Th17 cell polarization. In contrast, CTlo- or cAMP-DCs resembled semi-mature DCs and enhanced TGF-β-dependent Foxp3+ iTreg conversion. iTreg conversion could be reduced using siRNA blocking of CTLA-2 and reversely, addition of recombinant CTLA-2α increased iTreg conversion in vitro. Injection of CTlo- or cAMP-DCs exerted MOG peptide-specific protective effects in experimental autoimmune encephalomyelitis (EAE) by inducing Foxp3+ Tregs and reducing Th17 responses. Together, we identified CTLA-2 production by DCs as a novel tolerogenic mediator of TGF-β-mediated iTreg induction in vitro and in vivo. The CT-induced and cAMP-mediated up-regulation of CTLA-2 also may point to a novel immune evasion mechanism of Vibrio cholerae.

  @article{SilvaVilches:2017:PLoS-One:28759565, abstract = {Immature or semi-mature dendritic cells (DCs) represent tolerogenic maturation stages that can convert naive T cells into Foxp3+ induced regulatory T cells (iTreg). Here we found that murine bone marrow-derived DCs (BM-DCs) treated with cholera toxin (CT) matured by up-regulating MHC-II and costimulatory molecules using either high or low doses of CT (CThi, CTlo) or with cAMP, a known mediator CT signals. However, all three conditions also induced mRNA of both isoforms of the tolerogenic molecule cytotoxic T lymphocyte antigen 2 (CTLA-2α and CTLA-2β). Only DCs matured under CThi conditions secreted IL-1β, IL-6 and IL-23 leading to the instruction of Th17 cell polarization. In contrast, CTlo- or cAMP-DCs resembled semi-mature DCs and enhanced TGF-β-dependent Foxp3+ iTreg conversion. iTreg conversion could be reduced using siRNA blocking of CTLA-2 and reversely, addition of recombinant CTLA-2α increased iTreg conversion in vitro. Injection of CTlo- or cAMP-DCs exerted MOG peptide-specific protective effects in experimental autoimmune encephalomyelitis (EAE) by inducing Foxp3+ Tregs and reducing Th17 responses. Together, we identified CTLA-2 production by DCs as a novel tolerogenic mediator of TGF-β-mediated iTreg induction in vitro and in vivo. The CT-induced and cAMP-mediated up-regulation of CTLA-2 also may point to a novel immune evasion mechanism of Vibrio cholerae.}, author = {Silva-Vilches, C and Pletinckx, K and Lohnert, M and Pavlovic, V and Ashour, D and John, V and Vendelova, E and Kneitz, S and Zhou, J and Chen, R and Reinheckel, T and Mueller, T D and Bodem, J and Lutz, M B}, journal = {PLoS One}, keywords = {tdmueller}, number = 7, title = {Low doses of cholera toxin and its mediator cAMP induce CTLA-2 secretion by dendritic cells to enhance regulatory T cell conversion}, volume = 12, year = 2017 }

  %0 Journal Article %1 SilvaVilches:2017:PLoS-One:28759565 %A Silva-Vilches, C %A Pletinckx, K %A Lohnert, M %A Pavlovic, V %A Ashour, D %A John, V %A Vendelova, E %A Kneitz, S %A Zhou, J %A Chen, R %A Reinheckel, T %A Mueller, T D %A Bodem, J %A Lutz, M B %D 2017 %J PLoS One %N 7 %R 10.1371/journal.pone.0178114 %T Low doses of cholera toxin and its mediator cAMP induce CTLA-2 secretion by dendritic cells to enhance regulatory T cell conversion %U https://www.ncbi.nlm.nih.gov/pubmed/28759565 %V 12 %X Immature or semi-mature dendritic cells (DCs) represent tolerogenic maturation stages that can convert naive T cells into Foxp3+ induced regulatory T cells (iTreg). Here we found that murine bone marrow-derived DCs (BM-DCs) treated with cholera toxin (CT) matured by up-regulating MHC-II and costimulatory molecules using either high or low doses of CT (CThi, CTlo) or with cAMP, a known mediator CT signals. However, all three conditions also induced mRNA of both isoforms of the tolerogenic molecule cytotoxic T lymphocyte antigen 2 (CTLA-2α and CTLA-2β). Only DCs matured under CThi conditions secreted IL-1β, IL-6 and IL-23 leading to the instruction of Th17 cell polarization. In contrast, CTlo- or cAMP-DCs resembled semi-mature DCs and enhanced TGF-β-dependent Foxp3+ iTreg conversion. iTreg conversion could be reduced using siRNA blocking of CTLA-2 and reversely, addition of recombinant CTLA-2α increased iTreg conversion in vitro. Injection of CTlo- or cAMP-DCs exerted MOG peptide-specific protective effects in experimental autoimmune encephalomyelitis (EAE) by inducing Foxp3+ Tregs and reducing Th17 responses. Together, we identified CTLA-2 production by DCs as a novel tolerogenic mediator of TGF-β-mediated iTreg induction in vitro and in vivo. The CT-induced and cAMP-mediated up-regulation of CTLA-2 also may point to a novel immune evasion mechanism of Vibrio cholerae.
• Jodeleit, H., Palamides, P., Beigel, F., Mueller, T., Wolf, E., Siebeck, M., and Gropp, R. (2017) ‘Design and validation of a disease network of inflammatory processes in the NSG-UC mouse model’, J Transl Med, 15(1), 265–265, available: https://doi.org/10.1186/s12967-017-1368-4.
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  Ulcerative colitis (UC) is a highly progressive inflammatory disease that requires the interaction of epithelial, immune, endothelial and muscle cells and fibroblasts. Previous studies suggested two inflammatory conditions in UC-patients: 'acute' and 'remodeling' and that the design of a disease network might improve the understanding of the inflammatory processes. The objective of the study was to design and validate a disease network in the NOD-SCID IL2rγnull (NSG)-UC mouse model to get a better understanding of the inflammatory processes.Leukocytes were isolated from the spleen of NSG-UC mice and subjected to flow cytometric analysis. RT-PCR and RNAseq analysis were performed from distal parts of the colon. Based on these analyses and the effects of interleukins, chemokines and growth factors described in the literature, a disease network was designed. To validate the disease network the effect of infliximab and pitrakinra was tested in the NSG-UC model. A clinical- and histological score, frequencies of human leukocytes isolated from spleen and mRNA expression levels from distal parts of the colon were determined.Analysis of leukocytes isolated from the spleen of challenged NSG-UC mice corroborated CD64, CD163 and CD1a expressing CD14+ monocytes, CD1a expressing CD11b+ macrophages and HGF, TARC, IFNγ and TGFß1 mRNA as inflammatory markers. The disease network suggested that a proinflammatory condition elicited by IL-17c and lipids and relayed by cytotoxic T-cells, Th17 cells and CD1a expressing macrophages and monocytes. Conversely, the remodeling condition was evoked by IL-34 and TARC and promoted by Th2 cells and M2 monocytes. Mice benefitted from treatment with infliximab as indicated by the histological- and clinical score. As predicted by the disease network infliximab reduced the proinflammatory response by suppressing M1 monocytes and CD1a expressing monocytes and macrophages and decreased levels of IFNγ, TARC and HGF mRNA. As predicted by the disease network inflammation aggravated in the presence of pitrakinra as indicated by the clinical and histological score, elevated frequencies of CD1a expressing macrophages and TNFα and IFNγ mRNA levels.The combination of the disease network and the NSG-UC animal model might be developed into a powerful tool to predict efficacy or in-efficacy and potential mechanistic side effects.

  @article{Jodeleit:2017:J-Transl-Med:29282132, abstract = {Ulcerative colitis (UC) is a highly progressive inflammatory disease that requires the interaction of epithelial, immune, endothelial and muscle cells and fibroblasts. Previous studies suggested two inflammatory conditions in UC-patients: 'acute' and 'remodeling' and that the design of a disease network might improve the understanding of the inflammatory processes. The objective of the study was to design and validate a disease network in the NOD-SCID IL2rγnull (NSG)-UC mouse model to get a better understanding of the inflammatory processes.Leukocytes were isolated from the spleen of NSG-UC mice and subjected to flow cytometric analysis. RT-PCR and RNAseq analysis were performed from distal parts of the colon. Based on these analyses and the effects of interleukins, chemokines and growth factors described in the literature, a disease network was designed. To validate the disease network the effect of infliximab and pitrakinra was tested in the NSG-UC model. A clinical- and histological score, frequencies of human leukocytes isolated from spleen and mRNA expression levels from distal parts of the colon were determined.Analysis of leukocytes isolated from the spleen of challenged NSG-UC mice corroborated CD64, CD163 and CD1a expressing CD14+ monocytes, CD1a expressing CD11b+ macrophages and HGF, TARC, IFNγ and TGFß1 mRNA as inflammatory markers. The disease network suggested that a proinflammatory condition elicited by IL-17c and lipids and relayed by cytotoxic T-cells, Th17 cells and CD1a expressing macrophages and monocytes. Conversely, the remodeling condition was evoked by IL-34 and TARC and promoted by Th2 cells and M2 monocytes. Mice benefitted from treatment with infliximab as indicated by the histological- and clinical score. As predicted by the disease network infliximab reduced the proinflammatory response by suppressing M1 monocytes and CD1a expressing monocytes and macrophages and decreased levels of IFNγ, TARC and HGF mRNA. As predicted by the disease network inflammation aggravated in the presence of pitrakinra as indicated by the clinical and histological score, elevated frequencies of CD1a expressing macrophages and TNFα and IFNγ mRNA levels.The combination of the disease network and the NSG-UC animal model might be developed into a powerful tool to predict efficacy or in-efficacy and potential mechanistic side effects.}, author = {Jodeleit, H and Palamides, P and Beigel, F and Mueller, T and Wolf, E and Siebeck, M and Gropp, R}, journal = {J Transl Med}, keywords = {myown}, month = 12, number = 1, pages = {265-265}, title = {Design and validation of a disease network of inflammatory processes in the NSG-UC mouse model}, volume = 15, year = 2017 }

  %0 Journal Article %1 Jodeleit:2017:J-Transl-Med:29282132 %A Jodeleit, H %A Palamides, P %A Beigel, F %A Mueller, T %A Wolf, E %A Siebeck, M %A Gropp, R %D 2017 %J J Transl Med %N 1 %P 265-265 %R 10.1186/s12967-017-1368-4 %T Design and validation of a disease network of inflammatory processes in the NSG-UC mouse model %U https://www.ncbi.nlm.nih.gov/pubmed/29282132 %V 15 %X Ulcerative colitis (UC) is a highly progressive inflammatory disease that requires the interaction of epithelial, immune, endothelial and muscle cells and fibroblasts. Previous studies suggested two inflammatory conditions in UC-patients: 'acute' and 'remodeling' and that the design of a disease network might improve the understanding of the inflammatory processes. The objective of the study was to design and validate a disease network in the NOD-SCID IL2rγnull (NSG)-UC mouse model to get a better understanding of the inflammatory processes.Leukocytes were isolated from the spleen of NSG-UC mice and subjected to flow cytometric analysis. RT-PCR and RNAseq analysis were performed from distal parts of the colon. Based on these analyses and the effects of interleukins, chemokines and growth factors described in the literature, a disease network was designed. To validate the disease network the effect of infliximab and pitrakinra was tested in the NSG-UC model. A clinical- and histological score, frequencies of human leukocytes isolated from spleen and mRNA expression levels from distal parts of the colon were determined.Analysis of leukocytes isolated from the spleen of challenged NSG-UC mice corroborated CD64, CD163 and CD1a expressing CD14+ monocytes, CD1a expressing CD11b+ macrophages and HGF, TARC, IFNγ and TGFß1 mRNA as inflammatory markers. The disease network suggested that a proinflammatory condition elicited by IL-17c and lipids and relayed by cytotoxic T-cells, Th17 cells and CD1a expressing macrophages and monocytes. Conversely, the remodeling condition was evoked by IL-34 and TARC and promoted by Th2 cells and M2 monocytes. Mice benefitted from treatment with infliximab as indicated by the histological- and clinical score. As predicted by the disease network infliximab reduced the proinflammatory response by suppressing M1 monocytes and CD1a expressing monocytes and macrophages and decreased levels of IFNγ, TARC and HGF mRNA. As predicted by the disease network inflammation aggravated in the presence of pitrakinra as indicated by the clinical and histological score, elevated frequencies of CD1a expressing macrophages and TNFα and IFNγ mRNA levels.The combination of the disease network and the NSG-UC animal model might be developed into a powerful tool to predict efficacy or in-efficacy and potential mechanistic side effects.
• Tabisz, B., Schmitz, W., Schmitz, M., Luehmann, T., Heusler, E., Rybak, J.C., Meinel, L., Fiebig, J.E., Mueller, T.D., and Nickel, J. (2017) ‘Site-Directed Immobilization of BMP-2: Two Approaches for the Production of Innovative Osteoinductive Scaffolds’, Biomacromolecules, 18(3), 695–708, available: https://doi.org/10.1021/acs.biomac.6b01407.
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  @article{tabisz2017sitedirected, author = {Tabisz, B. and Schmitz, W. and Schmitz, M. and Luehmann, T. and Heusler, E. and Rybak, J. C. and Meinel, L. and Fiebig, J. E. and Mueller, T. D. and Nickel, J.}, journal = {Biomacromolecules}, keywords = {imported}, number = 3, pages = {695-708}, title = {Site-Directed Immobilization of BMP-2: Two Approaches for the Production of Innovative Osteoinductive Scaffolds}, type = {Journal Article}, volume = 18, year = 2017 }

  %0 Journal Article %1 tabisz2017sitedirected %A Tabisz, B. %A Schmitz, W. %A Schmitz, M. %A Luehmann, T. %A Heusler, E. %A Rybak, J. C. %A Meinel, L. %A Fiebig, J. E. %A Mueller, T. D. %A Nickel, J. %D 2017 %J Biomacromolecules %N 3 %P 695-708 %R 10.1021/acs.biomac.6b01407 %T Site-Directed Immobilization of BMP-2: Two Approaches for the Production of Innovative Osteoinductive Scaffolds %U https://www.ncbi.nlm.nih.gov/pubmed/28211679 %V 18
• Seher, A., Lagler, C., Stühmer, T., Müller-Richter, U.D.A., Kübler, A.C., Sebald, W., Müller, T.D., and Nickel, J. (2017) ‘Utilizing BMP-2 muteins for treatment of multiple myeloma’, PLOS ONE, 12(5), 1–18, available: https://doi.org/10.1371/journal.pone.0174884.
  • [ Abstract ]
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  Multiple myeloma (MM) represents a haematological cancer characterized by the pathological hyper proliferation of antibody-producing B-lymphocytes. Patients typically suffer from kidney malfunction and skeletal disorders. In the context of MM, the transforming growth factor β (TGFβ) member Activin A was recently identified as a promoter of both accompanying symptoms. Because studies have shown that bone morphogenetic protein (BMP)-2-mediated activities are counteracted by Activin A, we analysed whether BMP2, which also binds to the Activin A receptors ActRII and ActRIIB but activates the alternative SMAD-1/5/8 pathway, can be used to antagonize Activin A activities, such as in the context of MM. Therefore three BMP2 derivatives were generated with modified binding activities for the type II (ActRIIB) and/or type I receptor (BMPRIA) showing either increased or decreased BMP2 activity. In the context of MM these BMP2 muteins show two functionalities since they act as a) an anti-proliferative/apoptotic agent against neoplastic B-cells, b) as a bone-formation promoting growth factor. The molecular basis of both activities was shown in two different cellular models to clearly rely on the properties of the investigated BMP2 muteins to compete for the binding of Activin A to the Activin type II receptors. The experimental outcome suggests new therapeutic strategies using BMP2 variants in the treatment of MM-related pathologies.

  @article{10.1371/journal.pone.0174884, abstract = {Multiple myeloma (MM) represents a haematological cancer characterized by the pathological hyper proliferation of antibody-producing B-lymphocytes. Patients typically suffer from kidney malfunction and skeletal disorders. In the context of MM, the transforming growth factor β (TGFβ) member Activin A was recently identified as a promoter of both accompanying symptoms. Because studies have shown that bone morphogenetic protein (BMP)-2-mediated activities are counteracted by Activin A, we analysed whether BMP2, which also binds to the Activin A receptors ActRII and ActRIIB but activates the alternative SMAD-1/5/8 pathway, can be used to antagonize Activin A activities, such as in the context of MM. Therefore three BMP2 derivatives were generated with modified binding activities for the type II (ActRIIB) and/or type I receptor (BMPRIA) showing either increased or decreased BMP2 activity. In the context of MM these BMP2 muteins show two functionalities since they act as a) an anti-proliferative/apoptotic agent against neoplastic B-cells, b) as a bone-formation promoting growth factor. The molecular basis of both activities was shown in two different cellular models to clearly rely on the properties of the investigated BMP2 muteins to compete for the binding of Activin A to the Activin type II receptors. The experimental outcome suggests new therapeutic strategies using BMP2 variants in the treatment of MM-related pathologies.}, author = {Seher, Axel and Lagler, Charlotte and Stühmer, Thorsten and Müller-Richter, Urs Dietmar Achim and Kübler, Alexander Christian and Sebald, Walter and Müller, Thomas Dieter and Nickel, Joachim}, journal = {PLOS ONE}, keywords = {TGFbeta}, month = {05}, number = 5, pages = {1-18}, publisher = {Public Library of Science}, title = {Utilizing BMP-2 muteins for treatment of multiple myeloma}, volume = 12, year = 2017 }

  %0 Journal Article %1 10.1371/journal.pone.0174884 %A Seher, Axel %A Lagler, Charlotte %A Stühmer, Thorsten %A Müller-Richter, Urs Dietmar Achim %A Kübler, Alexander Christian %A Sebald, Walter %A Müller, Thomas Dieter %A Nickel, Joachim %D 2017 %I Public Library of Science %J PLOS ONE %N 5 %P 1-18 %R 10.1371/journal.pone.0174884 %T Utilizing BMP-2 muteins for treatment of multiple myeloma %U https://doi.org/10.1371/journal.pone.0174884 %V 12 %X Multiple myeloma (MM) represents a haematological cancer characterized by the pathological hyper proliferation of antibody-producing B-lymphocytes. Patients typically suffer from kidney malfunction and skeletal disorders. In the context of MM, the transforming growth factor β (TGFβ) member Activin A was recently identified as a promoter of both accompanying symptoms. Because studies have shown that bone morphogenetic protein (BMP)-2-mediated activities are counteracted by Activin A, we analysed whether BMP2, which also binds to the Activin A receptors ActRII and ActRIIB but activates the alternative SMAD-1/5/8 pathway, can be used to antagonize Activin A activities, such as in the context of MM. Therefore three BMP2 derivatives were generated with modified binding activities for the type II (ActRIIB) and/or type I receptor (BMPRIA) showing either increased or decreased BMP2 activity. In the context of MM these BMP2 muteins show two functionalities since they act as a) an anti-proliferative/apoptotic agent against neoplastic B-cells, b) as a bone-formation promoting growth factor. The molecular basis of both activities was shown in two different cellular models to clearly rely on the properties of the investigated BMP2 muteins to compete for the binding of Activin A to the Activin type II receptors. The experimental outcome suggests new therapeutic strategies using BMP2 variants in the treatment of MM-related pathologies.
• Richter, D., Moraga, I., Winkelmann, H., Birkholz, O., Wilmes, S., Schulte, M., Kraich, M., Kenneweg, H., Beutel, O., Selenschik, P., Paterok, D., Gavutis, M., Schmidt, T., Garcia, K.C., M{ü}ller, T.D., and Piehler, J. (2017) ‘Ligand-induced type II interleukin-4 receptor dimers are sustained by rapid re-association within plasma membrane microcompartments’, Nat Commun, 8, 15976–15976, available: https://doi.org/10.1038/ncomms15976.
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  The spatiotemporal organization of cytokine receptors in the plasma membrane is still debated with models ranging from ligand-independent receptor pre-dimerization to ligand-induced receptor dimerization occurring only after receptor uptake into endosomes. Here, we explore the molecular and cellular determinants governing the assembly of the type II interleukin-4 receptor, taking advantage of various agonists binding the receptor subunits with different affinities and rate constants. Quantitative kinetic studies using artificial membranes confirm that receptor dimerization is governed by the two-dimensional ligand-receptor interactions and identify a critical role of the transmembrane domain in receptor dimerization. Single molecule localization microscopy at physiological cell surface expression levels, however, reveals efficient ligand-induced receptor dimerization by all ligands, largely independent of receptor binding affinities, in line with the similar STAT6 activation potencies observed for all IL-4 variants. Detailed spatiotemporal analyses suggest that kinetic trapping of receptor dimers in actin-dependent microcompartments sustains robust receptor dimerization and signalling.

  @article{Richter:2017:Nat-Commun:28706306, abstract = {The spatiotemporal organization of cytokine receptors in the plasma membrane is still debated with models ranging from ligand-independent receptor pre-dimerization to ligand-induced receptor dimerization occurring only after receptor uptake into endosomes. Here, we explore the molecular and cellular determinants governing the assembly of the type II interleukin-4 receptor, taking advantage of various agonists binding the receptor subunits with different affinities and rate constants. Quantitative kinetic studies using artificial membranes confirm that receptor dimerization is governed by the two-dimensional ligand-receptor interactions and identify a critical role of the transmembrane domain in receptor dimerization. Single molecule localization microscopy at physiological cell surface expression levels, however, reveals efficient ligand-induced receptor dimerization by all ligands, largely independent of receptor binding affinities, in line with the similar STAT6 activation potencies observed for all IL-4 variants. Detailed spatiotemporal analyses suggest that kinetic trapping of receptor dimers in actin-dependent microcompartments sustains robust receptor dimerization and signalling.}, author = {Richter, D and Moraga, I and Winkelmann, H and Birkholz, O and Wilmes, S and Schulte, M and Kraich, M and Kenneweg, H and Beutel, O and Selenschik, P and Paterok, D and Gavutis, M and Schmidt, T and Garcia, K C and M{\"u}ller, T D and Piehler, J}, journal = {Nat Commun}, keywords = {myown}, month = {07}, pages = {15976-15976}, title = {Ligand-induced type II interleukin-4 receptor dimers are sustained by rapid re-association within plasma membrane microcompartments}, volume = 8, year = 2017 }

  %0 Journal Article %1 Richter:2017:Nat-Commun:28706306 %A Richter, D %A Moraga, I %A Winkelmann, H %A Birkholz, O %A Wilmes, S %A Schulte, M %A Kraich, M %A Kenneweg, H %A Beutel, O %A Selenschik, P %A Paterok, D %A Gavutis, M %A Schmidt, T %A Garcia, K C %A M{ü}ller, T D %A Piehler, J %D 2017 %J Nat Commun %P 15976-15976 %R 10.1038/ncomms15976 %T Ligand-induced type II interleukin-4 receptor dimers are sustained by rapid re-association within plasma membrane microcompartments %U https://www.ncbi.nlm.nih.gov/pubmed/28706306 %V 8 %X The spatiotemporal organization of cytokine receptors in the plasma membrane is still debated with models ranging from ligand-independent receptor pre-dimerization to ligand-induced receptor dimerization occurring only after receptor uptake into endosomes. Here, we explore the molecular and cellular determinants governing the assembly of the type II interleukin-4 receptor, taking advantage of various agonists binding the receptor subunits with different affinities and rate constants. Quantitative kinetic studies using artificial membranes confirm that receptor dimerization is governed by the two-dimensional ligand-receptor interactions and identify a critical role of the transmembrane domain in receptor dimerization. Single molecule localization microscopy at physiological cell surface expression levels, however, reveals efficient ligand-induced receptor dimerization by all ligands, largely independent of receptor binding affinities, in line with the similar STAT6 activation potencies observed for all IL-4 variants. Detailed spatiotemporal analyses suggest that kinetic trapping of receptor dimers in actin-dependent microcompartments sustains robust receptor dimerization and signalling.
• Lenglet, A., Jaślan, D., Toyota, M., Mueller, M., M{ü}ller, T., Sch{ö}nknecht, G., Marten, I., Gilroy, S., Hedrich, R., and Farmer, E.E. (2017) ‘Control of basal jasmonate signalling and defence through modulation of intracellular cation flux capacity’, New Phytol, 216(4), 1161–1169, available: https://doi.org/10.1111/nph.14754.
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  Unknown mechanisms tightly regulate the basal activity of the wound-inducible defence mediator jasmonate (JA) in undamaged tissues. However, the Arabidopsis fatty acid oxygenation upregulated2 (fou2) mutant in vacuolar two-pore channel 1 (TPC1D454N ) displays high JA pathway activity in undamaged leaves. This mutant was used to explore mechanisms controlling basal JA pathway regulation. fou2 was re-mutated to generate novel 'ouf' suppressor mutants. Patch-clamping was used to examine TPC1 cation channel characteristics in the ouf suppressor mutants and in fou2. Calcium (Ca2+ ) imaging was used to study the effects fou2 on cytosolic Ca2+ concentrations. Six intragenic ouf suppressors with near wild-type (WT) JA pathway activity were recovered and one mutant, ouf8, affected the channel pore. At low luminal calcium concentrations, ouf8 had little detectable effect on fou2. However, increased vacuolar Ca2+ concentrations caused channel occlusion, selectively blocking K+ fluxes towards the cytoplasm. Cytosolic Ca2+ concentrations in unwounded fou2 were found to be lower than in the unwounded WT, but they increased in a similar manner in both genotypes following wounding. Basal JA pathway activity can be controlled solely by manipulating endomembrane cation flux capacities. We suggest that changes in endomembrane potential affect JA pathway activity.

  @article{Lenglet:2017:New-Phytol:28885692, abstract = {Unknown mechanisms tightly regulate the basal activity of the wound-inducible defence mediator jasmonate (JA) in undamaged tissues. However, the Arabidopsis fatty acid oxygenation upregulated2 (fou2) mutant in vacuolar two-pore channel 1 (TPC1D454N ) displays high JA pathway activity in undamaged leaves. This mutant was used to explore mechanisms controlling basal JA pathway regulation. fou2 was re-mutated to generate novel 'ouf' suppressor mutants. Patch-clamping was used to examine TPC1 cation channel characteristics in the ouf suppressor mutants and in fou2. Calcium (Ca2+ ) imaging was used to study the effects fou2 on cytosolic Ca2+ concentrations. Six intragenic ouf suppressors with near wild-type (WT) JA pathway activity were recovered and one mutant, ouf8, affected the channel pore. At low luminal calcium concentrations, ouf8 had little detectable effect on fou2. However, increased vacuolar Ca2+ concentrations caused channel occlusion, selectively blocking K+ fluxes towards the cytoplasm. Cytosolic Ca2+ concentrations in unwounded fou2 were found to be lower than in the unwounded WT, but they increased in a similar manner in both genotypes following wounding. Basal JA pathway activity can be controlled solely by manipulating endomembrane cation flux capacities. We suggest that changes in endomembrane potential affect JA pathway activity.}, author = {Lenglet, A and Jaślan, D and Toyota, M and Mueller, M and M{\"u}ller, T and Sch{\"o}nknecht, G and Marten, I and Gilroy, S and Hedrich, R and Farmer, E E}, journal = {New Phytol}, keywords = {myown}, month = 12, number = 4, pages = {1161-1169}, title = {Control of basal jasmonate signalling and defence through modulation of intracellular cation flux capacity}, volume = 216, year = 2017 }

  %0 Journal Article %1 Lenglet:2017:New-Phytol:28885692 %A Lenglet, A %A Jaślan, D %A Toyota, M %A Mueller, M %A M{ü}ller, T %A Sch{ö}nknecht, G %A Marten, I %A Gilroy, S %A Hedrich, R %A Farmer, E E %D 2017 %J New Phytol %N 4 %P 1161-1169 %R 10.1111/nph.14754 %T Control of basal jasmonate signalling and defence through modulation of intracellular cation flux capacity %U https://www.ncbi.nlm.nih.gov/pubmed/28885692 %V 216 %X Unknown mechanisms tightly regulate the basal activity of the wound-inducible defence mediator jasmonate (JA) in undamaged tissues. However, the Arabidopsis fatty acid oxygenation upregulated2 (fou2) mutant in vacuolar two-pore channel 1 (TPC1D454N ) displays high JA pathway activity in undamaged leaves. This mutant was used to explore mechanisms controlling basal JA pathway regulation. fou2 was re-mutated to generate novel 'ouf' suppressor mutants. Patch-clamping was used to examine TPC1 cation channel characteristics in the ouf suppressor mutants and in fou2. Calcium (Ca2+ ) imaging was used to study the effects fou2 on cytosolic Ca2+ concentrations. Six intragenic ouf suppressors with near wild-type (WT) JA pathway activity were recovered and one mutant, ouf8, affected the channel pore. At low luminal calcium concentrations, ouf8 had little detectable effect on fou2. However, increased vacuolar Ca2+ concentrations caused channel occlusion, selectively blocking K+ fluxes towards the cytoplasm. Cytosolic Ca2+ concentrations in unwounded fou2 were found to be lower than in the unwounded WT, but they increased in a similar manner in both genotypes following wounding. Basal JA pathway activity can be controlled solely by manipulating endomembrane cation flux capacities. We suggest that changes in endomembrane potential affect JA pathway activity.

• Boschert, V., Frisch, C., Back, J.W., van Pee, K., Weidauer, S.E., Muth, E.M., Schmieder, P., Beerbaum, M., Knappik, A., Timmerman, P., and Mueller, T.D. (2016) ‘The sclerostin-neutralizing antibody AbD09097 recognizes an epitope adjacent to sclerostin’s binding site for the Wnt co-receptor LRP6’, Open Biol, 6(8), available: https://doi.org/10.1098/rsob.160120.
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  @article{boschert2016sclerostinneutralizing, author = {Boschert, V. and Frisch, C. and Back, J. W. and van Pee, K. and Weidauer, S. E. and Muth, E. M. and Schmieder, P. and Beerbaum, M. and Knappik, A. and Timmerman, P. and Mueller, T. D.}, journal = {Open Biol}, keywords = {tdmueller}, number = 8, title = {The sclerostin-neutralizing antibody AbD09097 recognizes an epitope adjacent to sclerostin's binding site for the Wnt co-receptor LRP6}, type = {Journal Article}, volume = 6, year = 2016 }

  %0 Journal Article %1 boschert2016sclerostinneutralizing %A Boschert, V. %A Frisch, C. %A Back, J. W. %A van Pee, K. %A Weidauer, S. E. %A Muth, E. M. %A Schmieder, P. %A Beerbaum, M. %A Knappik, A. %A Timmerman, P. %A Mueller, T. D. %D 2016 %J Open Biol %N 8 %R 10.1098/rsob.160120 %T The sclerostin-neutralizing antibody AbD09097 recognizes an epitope adjacent to sclerostin's binding site for the Wnt co-receptor LRP6 %U https://www.ncbi.nlm.nih.gov/pubmed/27558933 %V 6
• Bohm, J., Scherzer, S., Krol, E., Kreuzer, I., von Meyer, K., Lorey, C., Mueller, T.D., Shabala, L., Monte, I., Solano, R., Al-Rasheid, K.A., Rennenberg, H., Shabala, S., Neher, E., and Hedrich, R. (2016) ‘The Venus Flytrap Dionaea muscipula Counts Prey-Induced Action Potentials to Induce Sodium Uptake’, Curr Biol, 26(3), 286–95, available: https://doi.org/10.1016/j.cub.2015.11.057.
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  @article{bohm2016venus, author = {Bohm, J. and Scherzer, S. and Krol, E. and Kreuzer, I. and von Meyer, K. and Lorey, C. and Mueller, T. D. and Shabala, L. and Monte, I. and Solano, R. and Al-Rasheid, K. A. and Rennenberg, H. and Shabala, S. and Neher, E. and Hedrich, R.}, journal = {Curr Biol}, keywords = {tdmueller}, number = 3, pages = {286-95}, title = {The Venus Flytrap Dionaea muscipula Counts Prey-Induced Action Potentials to Induce Sodium Uptake}, type = {Journal Article}, volume = 26, year = 2016 }

  %0 Journal Article %1 bohm2016venus %A Bohm, J. %A Scherzer, S. %A Krol, E. %A Kreuzer, I. %A von Meyer, K. %A Lorey, C. %A Mueller, T. D. %A Shabala, L. %A Monte, I. %A Solano, R. %A Al-Rasheid, K. A. %A Rennenberg, H. %A Shabala, S. %A Neher, E. %A Hedrich, R. %D 2016 %J Curr Biol %N 3 %P 286-95 %R 10.1016/j.cub.2015.11.057 %T The Venus Flytrap Dionaea muscipula Counts Prey-Induced Action Potentials to Induce Sodium Uptake %U https://www.ncbi.nlm.nih.gov/pubmed/26804557 %V 26
• Jaslan, D., Mueller, T.D., Becker, D., Schultz, J., Cuin, T.A., Marten, I., Dreyer, I., Schonknecht, G., and Hedrich, R. (2016) ‘Gating of the two-pore cation channel AtTPC1 in the plant vacuole is based on a single voltage-sensing domain’, Plant Biol (Stuttg), 18(5), 750–60, available: https://doi.org/10.1111/plb.12478.
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  @article{jaslan2016gating, author = {Jaslan, D. and Mueller, T. D. and Becker, D. and Schultz, J. and Cuin, T. A. and Marten, I. and Dreyer, I. and Schonknecht, G. and Hedrich, R.}, journal = {Plant Biol (Stuttg)}, keywords = {imported}, number = 5, pages = {750-60}, title = {Gating of the two-pore cation channel AtTPC1 in the plant vacuole is based on a single voltage-sensing domain}, type = {Journal Article}, volume = 18, year = 2016 }

  %0 Journal Article %1 jaslan2016gating %A Jaslan, D. %A Mueller, T. D. %A Becker, D. %A Schultz, J. %A Cuin, T. A. %A Marten, I. %A Dreyer, I. %A Schonknecht, G. %A Hedrich, R. %D 2016 %J Plant Biol (Stuttg) %N 5 %P 750-60 %R 10.1111/plb.12478 %T Gating of the two-pore cation channel AtTPC1 in the plant vacuole is based on a single voltage-sensing domain %U https://www.ncbi.nlm.nih.gov/pubmed/27270880 %V 18
• Hinck, A.P., Mueller, T.D., and Springer, T.A. (2016) ‘Structural Biology and Evolution of the TGF-beta Family’, Cold Spring Harb Perspect Biol, 8(12), available: https://doi.org/10.1101/cshperspect.a022103.
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  @article{hinck2016structural, author = {Hinck, A. P. and Mueller, T. D. and Springer, T. A.}, journal = {Cold Spring Harb Perspect Biol}, keywords = {imported}, number = 12, title = {Structural Biology and Evolution of the TGF-beta Family}, type = {Journal Article}, volume = 8, year = 2016 }

  %0 Journal Article %1 hinck2016structural %A Hinck, A. P. %A Mueller, T. D. %A Springer, T. A. %D 2016 %J Cold Spring Harb Perspect Biol %N 12 %R 10.1101/cshperspect.a022103 %T Structural Biology and Evolution of the TGF-beta Family %U https://www.ncbi.nlm.nih.gov/pubmed/27638177 %V 8
• Chintalapati, C., Keller, T., Mueller, T.D., Gorboulev, V., Schafer, N., Zilkowski, I., Veyhl-Wichmann, M., Geiger, D., Groll, J., and Koepsell, H. (2016) ‘Protein RS1 (RSC1A1) Downregulates the Exocytotic Pathway of Glucose Transporter SGLT1 at Low Intracellular Glucose via Inhibition of Ornithine Decarboxylase’, Mol Pharmacol, 90(5), 508–521, available: https://doi.org/10.1124/mol.116.104521.
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  @article{chintalapati2016protein, author = {Chintalapati, C. and Keller, T. and Mueller, T. D. and Gorboulev, V. and Schafer, N. and Zilkowski, I. and Veyhl-Wichmann, M. and Geiger, D. and Groll, J. and Koepsell, H.}, journal = {Mol Pharmacol}, keywords = {imported}, number = 5, pages = {508-521}, title = {Protein RS1 (RSC1A1) Downregulates the Exocytotic Pathway of Glucose Transporter SGLT1 at Low Intracellular Glucose via Inhibition of Ornithine Decarboxylase}, type = {Journal Article}, volume = 90, year = 2016 }

  %0 Journal Article %1 chintalapati2016protein %A Chintalapati, C. %A Keller, T. %A Mueller, T. D. %A Gorboulev, V. %A Schafer, N. %A Zilkowski, I. %A Veyhl-Wichmann, M. %A Geiger, D. %A Groll, J. %A Koepsell, H. %D 2016 %J Mol Pharmacol %N 5 %P 508-521 %R 10.1124/mol.116.104521 %T Protein RS1 (RSC1A1) Downregulates the Exocytotic Pathway of Glucose Transporter SGLT1 at Low Intracellular Glucose via Inhibition of Ornithine Decarboxylase %U https://www.ncbi.nlm.nih.gov/pubmed/27555600 %V 90
• Schindler, R.F., Scotton, C., Zhang, J., Passarelli, C., Ortiz-Bonnin, B., Simrick, S., Schwerte, T., Poon, K.L., Fang, M., Rinne, S., Froese, A., Nikolaev, V.O., Grunert, C., Muller, T., Tasca, G., Sarathchandra, P., Drago, F., Dallapiccola, B., Rapezzi, C., Arbustini, E., Di Raimo, F.R., Neri, M., Selvatici, R., Gualandi, F., Fattori, F., Pietrangelo, A., Li, W., Jiang, H., Xu, X., Bertini, E., Decher, N., Wang, J., Brand, T., and Ferlini, A. (2016) ‘POPDC1(S201F) causes muscular dystrophy and arrhythmia by affecting protein trafficking’, J Clin Invest, 126(1), 239–53, available: https://doi.org/10.1172/JCI79562.
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  @article{schindler2016popdc1s201f, author = {Schindler, R. F. and Scotton, C. and Zhang, J. and Passarelli, C. and Ortiz-Bonnin, B. and Simrick, S. and Schwerte, T. and Poon, K. L. and Fang, M. and Rinne, S. and Froese, A. and Nikolaev, V. O. and Grunert, C. and Muller, T. and Tasca, G. and Sarathchandra, P. and Drago, F. and Dallapiccola, B. and Rapezzi, C. and Arbustini, E. and Di Raimo, F. R. and Neri, M. and Selvatici, R. and Gualandi, F. and Fattori, F. and Pietrangelo, A. and Li, W. and Jiang, H. and Xu, X. and Bertini, E. and Decher, N. and Wang, J. and Brand, T. and Ferlini, A.}, journal = {J Clin Invest}, keywords = {imported}, number = 1, pages = {239-53}, title = {POPDC1(S201F) causes muscular dystrophy and arrhythmia by affecting protein trafficking}, type = {Journal Article}, volume = 126, year = 2016 }

  %0 Journal Article %1 schindler2016popdc1s201f %A Schindler, R. F. %A Scotton, C. %A Zhang, J. %A Passarelli, C. %A Ortiz-Bonnin, B. %A Simrick, S. %A Schwerte, T. %A Poon, K. L. %A Fang, M. %A Rinne, S. %A Froese, A. %A Nikolaev, V. O. %A Grunert, C. %A Muller, T. %A Tasca, G. %A Sarathchandra, P. %A Drago, F. %A Dallapiccola, B. %A Rapezzi, C. %A Arbustini, E. %A Di Raimo, F. R. %A Neri, M. %A Selvatici, R. %A Gualandi, F. %A Fattori, F. %A Pietrangelo, A. %A Li, W. %A Jiang, H. %A Xu, X. %A Bertini, E. %A Decher, N. %A Wang, J. %A Brand, T. %A Ferlini, A. %D 2016 %J J Clin Invest %N 1 %P 239-53 %R 10.1172/JCI79562 %T POPDC1(S201F) causes muscular dystrophy and arrhythmia by affecting protein trafficking %U https://www.ncbi.nlm.nih.gov/pubmed/26642364 %V 126
• Palamides, P., Jodeleit, H., Fohlinger, M., Beigel, F., Herbach, N., Mueller, T., Wolf, E., Siebeck, M., and Gropp, R. (2016) ‘A mouse model for ulcerative colitis based on NOD-scid IL2R gammanull mice reconstituted with peripheral blood mononuclear cells from affected individuals’, Dis Model Mech, 9(9), 985–97, available: https://doi.org/10.1242/dmm.025452.
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  @article{palamides2016mouse, author = {Palamides, P. and Jodeleit, H. and Fohlinger, M. and Beigel, F. and Herbach, N. and Mueller, T. and Wolf, E. and Siebeck, M. and Gropp, R.}, journal = {Dis Model Mech}, keywords = {imported}, number = 9, pages = {985-97}, title = {A mouse model for ulcerative colitis based on NOD-scid IL2R gammanull mice reconstituted with peripheral blood mononuclear cells from affected individuals}, type = {Journal Article}, volume = 9, year = 2016 }

  %0 Journal Article %1 palamides2016mouse %A Palamides, P. %A Jodeleit, H. %A Fohlinger, M. %A Beigel, F. %A Herbach, N. %A Mueller, T. %A Wolf, E. %A Siebeck, M. %A Gropp, R. %D 2016 %J Dis Model Mech %N 9 %P 985-97 %R 10.1242/dmm.025452 %T A mouse model for ulcerative colitis based on NOD-scid IL2R gammanull mice reconstituted with peripheral blood mononuclear cells from affected individuals %U https://www.ncbi.nlm.nih.gov/pubmed/27491073 %V 9
• Yadin, D., Knaus, P., and Mueller, T.D. (2016) ‘Structural insights into BMP receptors: Specificity, activation and inhibition’, Cytokine Growth Factor Rev, 27, 13–34, available: https://doi.org/10.1016/j.cytogfr.2015.11.005.
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  @article{yadin2016structural, author = {Yadin, D. and Knaus, P. and Mueller, T. D.}, journal = {Cytokine Growth Factor Rev}, keywords = {tdmueller}, pages = {13-34}, title = {Structural insights into BMP receptors: Specificity, activation and inhibition}, type = {Journal Article}, volume = 27, year = 2016 }

  %0 Journal Article %1 yadin2016structural %A Yadin, D. %A Knaus, P. %A Mueller, T. D. %D 2016 %J Cytokine Growth Factor Rev %P 13-34 %R 10.1016/j.cytogfr.2015.11.005 %T Structural insights into BMP receptors: Specificity, activation and inhibition %U https://www.ncbi.nlm.nih.gov/pubmed/26690041 %V 27
• Deeken, R., Saupe, S., Klinkenberg, J., Riedel, M., Leide, J., Hedrich, R., and Mueller, T.D. (2016) ‘The Nonspecific Lipid Transfer Protein AtLtpI-4 Is Involved in Suberin Formation of Arabidopsis thaliana Crown Galls’, Plant Physiol, 172(3), 1911–1927, available: https://doi.org/10.1104/pp.16.01486.
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  @article{deeken2016nonspecific, author = {Deeken, R. and Saupe, S. and Klinkenberg, J. and Riedel, M. and Leide, J. and Hedrich, R. and Mueller, T. D.}, journal = {Plant Physiol}, keywords = {imported}, number = 3, pages = {1911-1927}, title = {The Nonspecific Lipid Transfer Protein AtLtpI-4 Is Involved in Suberin Formation of Arabidopsis thaliana Crown Galls}, type = {Journal Article}, volume = 172, year = 2016 }

  %0 Journal Article %1 deeken2016nonspecific %A Deeken, R. %A Saupe, S. %A Klinkenberg, J. %A Riedel, M. %A Leide, J. %A Hedrich, R. %A Mueller, T. D. %D 2016 %J Plant Physiol %N 3 %P 1911-1927 %R 10.1104/pp.16.01486 %T The Nonspecific Lipid Transfer Protein AtLtpI-4 Is Involved in Suberin Formation of Arabidopsis thaliana Crown Galls %U https://www.ncbi.nlm.nih.gov/pubmed/27688623 %V 172
• Johnson, K.E., Makanji, Y., Temple-Smith, P., Kelly, E.K., Barton, P.A., Al-Musawi, S.L., Mueller, T.D., Walton, K.L., and Harrison, C.A. (2016) ‘Biological activity and in vivo half-life of pro-activin A in male rats’, Mol Cell Endocrinol, 422, 84–92, available: https://doi.org/10.1016/j.mce.2015.12.007.
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  @article{johnson2016biological, author = {Johnson, K. E. and Makanji, Y. and Temple-Smith, P. and Kelly, E. K. and Barton, P. A. and Al-Musawi, S. L. and Mueller, T. D. and Walton, K. L. and Harrison, C. A.}, journal = {Mol Cell Endocrinol}, keywords = {imported}, pages = {84-92}, title = {Biological activity and in vivo half-life of pro-activin A in male rats}, type = {Journal Article}, volume = 422, year = 2016 }

  %0 Journal Article %1 johnson2016biological %A Johnson, K. E. %A Makanji, Y. %A Temple-Smith, P. %A Kelly, E. K. %A Barton, P. A. %A Al-Musawi, S. L. %A Mueller, T. D. %A Walton, K. L. %A Harrison, C. A. %D 2016 %J Mol Cell Endocrinol %P 84-92 %R 10.1016/j.mce.2015.12.007 %T Biological activity and in vivo half-life of pro-activin A in male rats %U http://www.ncbi.nlm.nih.gov/pubmed/26687063 %V 422
• Luhmann, T., Spieler, V., Werner, V., Ludwig, M.G., Fiebig, J., Mueller, T.D., and Meinel, L. (2016) ‘Interleukin-4-Clicked Surfaces Drive M2 Macrophage Polarization’, Chembiochem, 17(22), 2123–2128, available: https://doi.org/10.1002/cbic.201600480.
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  @article{luhmann2016interleukin4clicked, author = {Luhmann, T. and Spieler, V. and Werner, V. and Ludwig, M. G. and Fiebig, J. and Mueller, T. D. and Meinel, L.}, journal = {Chembiochem}, keywords = {imported}, number = 22, pages = {2123-2128}, title = {Interleukin-4-Clicked Surfaces Drive M2 Macrophage Polarization}, type = {Journal Article}, volume = 17, year = 2016 }

  %0 Journal Article %1 luhmann2016interleukin4clicked %A Luhmann, T. %A Spieler, V. %A Werner, V. %A Ludwig, M. G. %A Fiebig, J. %A Mueller, T. D. %A Meinel, L. %D 2016 %J Chembiochem %N 22 %P 2123-2128 %R 10.1002/cbic.201600480 %T Interleukin-4-Clicked Surfaces Drive M2 Macrophage Polarization %U https://www.ncbi.nlm.nih.gov/pubmed/27595549 %V 17
• Bohm, J., Scherzer, S., Shabala, S., Krol, E., Neher, E., Mueller, T.D., and Hedrich, R. (2016) ‘Venus Flytrap HKT1-Type Channel Provides for Prey Sodium Uptake into Carnivorous Plant Without Conflicting with Electrical Excitability’, Mol Plant, 9(3), 428–36, available: https://doi.org/10.1016/j.molp.2015.09.017.
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  @article{bohm2016venus, author = {Bohm, J. and Scherzer, S. and Shabala, S. and Krol, E. and Neher, E. and Mueller, T. D. and Hedrich, R.}, journal = {Mol Plant}, keywords = {imported}, number = 3, pages = {428-36}, title = {Venus Flytrap HKT1-Type Channel Provides for Prey Sodium Uptake into Carnivorous Plant Without Conflicting with Electrical Excitability}, type = {Journal Article}, volume = 9, year = 2016 }

  %0 Journal Article %1 bohm2016venus %A Bohm, J. %A Scherzer, S. %A Shabala, S. %A Krol, E. %A Neher, E. %A Mueller, T. D. %A Hedrich, R. %D 2016 %J Mol Plant %N 3 %P 428-36 %R 10.1016/j.molp.2015.09.017 %T Venus Flytrap HKT1-Type Channel Provides for Prey Sodium Uptake into Carnivorous Plant Without Conflicting with Electrical Excitability %U https://www.ncbi.nlm.nih.gov/pubmed/26455461 %V 9
• Chopra, M., Biehl, M., Steinfatt, T., Brandl, A., Kums, J., Amich, J., Vaeth, M., Kuen, J., Holtappels, R., Podlech, J., Mottok, A., Kraus, S., Jordan-Garrote, A.L., Bauerlein, C.A., Brede, C., Ribechini, E., Fick, A., Seher, A., Polz, J., Ottmuller, K.J., Baker, J., Nishikii, H., Ritz, M., Mattenheimer, K., Schwinn, S., Winter, T., Schafer, V., Krappmann, S., Einsele, H., Muller, T.D., Reddehase, M.J., Lutz, M.B., Mannel, D.N., Berberich-Siebelt, F., Wajant, H., and Beilhack, A. (2016) ‘Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion’, J Exp Med, 213(9), 1881–900, available: https://doi.org/10.1084/jem.20151563.
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  @article{chopra2016exogenous, author = {Chopra, M. and Biehl, M. and Steinfatt, T. and Brandl, A. and Kums, J. and Amich, J. and Vaeth, M. and Kuen, J. and Holtappels, R. and Podlech, J. and Mottok, A. and Kraus, S. and Jordan-Garrote, A. L. and Bauerlein, C. A. and Brede, C. and Ribechini, E. and Fick, A. and Seher, A. and Polz, J. and Ottmuller, K. J. and Baker, J. and Nishikii, H. and Ritz, M. and Mattenheimer, K. and Schwinn, S. and Winter, T. and Schafer, V. and Krappmann, S. and Einsele, H. and Muller, T. D. and Reddehase, M. J. and Lutz, M. B. and Mannel, D. N. and Berberich-Siebelt, F. and Wajant, H. and Beilhack, A.}, journal = {J Exp Med}, keywords = {tdmueller}, number = 9, pages = {1881-900}, title = {Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion}, type = {Journal Article}, volume = 213, year = 2016 }

  %0 Journal Article %1 chopra2016exogenous %A Chopra, M. %A Biehl, M. %A Steinfatt, T. %A Brandl, A. %A Kums, J. %A Amich, J. %A Vaeth, M. %A Kuen, J. %A Holtappels, R. %A Podlech, J. %A Mottok, A. %A Kraus, S. %A Jordan-Garrote, A. L. %A Bauerlein, C. A. %A Brede, C. %A Ribechini, E. %A Fick, A. %A Seher, A. %A Polz, J. %A Ottmuller, K. J. %A Baker, J. %A Nishikii, H. %A Ritz, M. %A Mattenheimer, K. %A Schwinn, S. %A Winter, T. %A Schafer, V. %A Krappmann, S. %A Einsele, H. %A Muller, T. D. %A Reddehase, M. J. %A Lutz, M. B. %A Mannel, D. N. %A Berberich-Siebelt, F. %A Wajant, H. %A Beilhack, A. %D 2016 %J J Exp Med %N 9 %P 1881-900 %R 10.1084/jem.20151563 %T Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion %U https://www.ncbi.nlm.nih.gov/pubmed/27526711 %V 213
• Paarmann, P., Dorpholz, G., Fiebig, J., Amsalem, A.R., Ehrlich, M., Henis, Y.I., Muller, T., and Knaus, P. (2016) ‘Dynamin-dependent endocytosis of Bone Morphogenetic Protein2 (BMP2) and its receptors is dispensable for the initiation of Smad signaling’, Int J Biochem Cell Biol, 76, 51–63, available: https://doi.org/10.1016/j.biocel.2016.04.010.
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  @article{paarmann2016dynamindependent, author = {Paarmann, P. and Dorpholz, G. and Fiebig, J. and Amsalem, A. R. and Ehrlich, M. and Henis, Y. I. and Muller, T. and Knaus, P.}, journal = {Int J Biochem Cell Biol}, keywords = {imported}, pages = {51-63}, title = {Dynamin-dependent endocytosis of Bone Morphogenetic Protein2 (BMP2) and its receptors is dispensable for the initiation of Smad signaling}, type = {Journal Article}, volume = 76, year = 2016 }

  %0 Journal Article %1 paarmann2016dynamindependent %A Paarmann, P. %A Dorpholz, G. %A Fiebig, J. %A Amsalem, A. R. %A Ehrlich, M. %A Henis, Y. I. %A Muller, T. %A Knaus, P. %D 2016 %J Int J Biochem Cell Biol %P 51-63 %R 10.1016/j.biocel.2016.04.010 %T Dynamin-dependent endocytosis of Bone Morphogenetic Protein2 (BMP2) and its receptors is dispensable for the initiation of Smad signaling %U https://www.ncbi.nlm.nih.gov/pubmed/27113717 %V 76
• Vendelova, E., Camargo de Lima, J., Lorenzatto, K.R., Monteiro, K.M., Mueller, T., Veepaschit, J., Grimm, C., Brehm, K., Hrckova, G., Lutz, M.B., Ferreira, H.B., and Nono, J.K. (2016) ‘Proteomic Analysis of Excretory-Secretory Products of Mesocestoides corti Metacestodes Reveals Potential Suppressors of Dendritic Cell Functions’, PLoS Negl Trop Dis, 10(10), e0005061, available: https://doi.org/10.1371/journal.pntd.0005061.
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  @article{vendelova2016proteomic, author = {Vendelova, E. and Camargo de Lima, J. and Lorenzatto, K. R. and Monteiro, K. M. and Mueller, T. and Veepaschit, J. and Grimm, C. and Brehm, K. and Hrckova, G. and Lutz, M. B. and Ferreira, H. B. and Nono, J. K.}, journal = {PLoS Negl Trop Dis}, keywords = {imported}, number = 10, pages = {e0005061}, title = {Proteomic Analysis of Excretory-Secretory Products of Mesocestoides corti Metacestodes Reveals Potential Suppressors of Dendritic Cell Functions}, type = {Journal Article}, volume = 10, year = 2016 }

  %0 Journal Article %1 vendelova2016proteomic %A Vendelova, E. %A Camargo de Lima, J. %A Lorenzatto, K. R. %A Monteiro, K. M. %A Mueller, T. %A Veepaschit, J. %A Grimm, C. %A Brehm, K. %A Hrckova, G. %A Lutz, M. B. %A Ferreira, H. B. %A Nono, J. K. %D 2016 %J PLoS Negl Trop Dis %N 10 %P e0005061 %R 10.1371/journal.pntd.0005061 %T Proteomic Analysis of Excretory-Secretory Products of Mesocestoides corti Metacestodes Reveals Potential Suppressors of Dendritic Cell Functions %U https://www.ncbi.nlm.nih.gov/pubmed/27736880 %V 10

• Mueller, T.D. (2015) ‘Mechanisms of BMP-Receptor Interaction and Activation’, Vitam Horm, 99, 1–61, available: https://doi.org/10.1016/bs.vh.2015.06.003.
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  @article{mueller2015mechanisms, author = {Mueller, T. D.}, journal = {Vitam Horm}, keywords = {imported}, pages = {1-61}, title = {Mechanisms of BMP-Receptor Interaction and Activation}, type = {Journal Article}, volume = 99, year = 2015 }

  %0 Journal Article %1 mueller2015mechanisms %A Mueller, T. D. %D 2015 %J Vitam Horm %P 1-61 %R 10.1016/bs.vh.2015.06.003 %T Mechanisms of BMP-Receptor Interaction and Activation %U http://www.ncbi.nlm.nih.gov/pubmed/26279372 %V 99
• Li, J.J., Sugimura, S., Mueller, T.D., White, M.A., Martin, G.A., Ritter, L.J., Liang, X.Y., Gilchrist, R.B., and Mottershead, D.G. (2015) ‘Modifications of human growth differentiation factor 9 to improve the generation of embryos from low competence oocytes’, Mol Endocrinol, 29(1), 40–52, available: https://doi.org/10.1210/me.2014-1173.
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  @article{li2015modifications, author = {Li, J. J. and Sugimura, S. and Mueller, T. D. and White, M. A. and Martin, G. A. and Ritter, L. J. and Liang, X. Y. and Gilchrist, R. B. and Mottershead, D. G.}, journal = {Mol Endocrinol}, keywords = {imported}, number = 1, pages = {40-52}, title = {Modifications of human growth differentiation factor 9 to improve the generation of embryos from low competence oocytes}, type = {Journal Article}, volume = 29, year = 2015 }

  %0 Journal Article %1 li2015modifications %A Li, J. J. %A Sugimura, S. %A Mueller, T. D. %A White, M. A. %A Martin, G. A. %A Ritter, L. J. %A Liang, X. Y. %A Gilchrist, R. B. %A Mottershead, D. G. %D 2015 %J Mol Endocrinol %N 1 %P 40-52 %R 10.1210/me.2014-1173 %T Modifications of human growth differentiation factor 9 to improve the generation of embryos from low competence oocytes %U http://www.ncbi.nlm.nih.gov/pubmed/25394262 %V 29
• Paletta, D., Fichtner, A.S., Hahn, A.M., Starick, L., Beyersdorf, N., Monzon-Casanova, E., Mueller, T.D., and Herrmann, T. (2015) ‘The hypervariable region 4 (HV4) and position 93 of the alpha chain modulate CD1d-glycolipid binding of iNKT TCRs’, Eur J Immunol, 45(7), 2122–33, available: https://doi.org/10.1002/eji.201545534.
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  @article{paletta2015hypervariable, author = {Paletta, D. and Fichtner, A. S. and Hahn, A. M. and Starick, L. and Beyersdorf, N. and Monzon-Casanova, E. and Mueller, T. D. and Herrmann, T.}, journal = {Eur J Immunol}, keywords = {imported}, number = 7, pages = {2122-33}, title = {The hypervariable region 4 (HV4) and position 93 of the alpha chain modulate CD1d-glycolipid binding of iNKT TCRs}, type = {Journal Article}, volume = 45, year = 2015 }

  %0 Journal Article %1 paletta2015hypervariable %A Paletta, D. %A Fichtner, A. S. %A Hahn, A. M. %A Starick, L. %A Beyersdorf, N. %A Monzon-Casanova, E. %A Mueller, T. D. %A Herrmann, T. %D 2015 %J Eur J Immunol %N 7 %P 2122-33 %R 10.1002/eji.201545534 %T The hypervariable region 4 (HV4) and position 93 of the alpha chain modulate CD1d-glycolipid binding of iNKT TCRs %U http://www.ncbi.nlm.nih.gov/pubmed/25900449 %V 45
• Mueller, T.D. (2015) ‘RGM co-receptors add complexity to BMP signaling’, Nat Struct Mol Biol, 22(6), 439–40, available: https://doi.org/10.1038/nsmb.3037.
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  @article{mueller2015coreceptors, author = {Mueller, T. D.}, journal = {Nat Struct Mol Biol}, keywords = {imported}, number = 6, pages = {439-40}, title = {RGM co-receptors add complexity to BMP signaling}, type = {Journal Article}, volume = 22, year = 2015 }

  %0 Journal Article %1 mueller2015coreceptors %A Mueller, T. D. %D 2015 %J Nat Struct Mol Biol %N 6 %P 439-40 %R 10.1038/nsmb.3037 %T RGM co-receptors add complexity to BMP signaling %U http://www.ncbi.nlm.nih.gov/pubmed/26036568 %V 22
• Bohm, J., Scherzer, S., Shabala, S., Krol, E., Neher, E., Mueller, T.D., and Hedrich, R. (2015) ‘Venus Flytrap HKT1-Type Channel Provides for Prey Sodium Uptake into Carnivorous Plant Without Conflicting with Electrical Excitability’, Mol Plant, available: https://doi.org/10.1016/j.molp.2015.09.017.
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  @article{bohm2015venus, author = {Bohm, J. and Scherzer, S. and Shabala, S. and Krol, E. and Neher, E. and Mueller, T. D. and Hedrich, R.}, journal = {Mol Plant}, keywords = {imported}, title = {Venus Flytrap HKT1-Type Channel Provides for Prey Sodium Uptake into Carnivorous Plant Without Conflicting with Electrical Excitability}, type = {Journal Article}, year = 2015 }

  %0 Journal Article %1 bohm2015venus %A Bohm, J. %A Scherzer, S. %A Shabala, S. %A Krol, E. %A Neher, E. %A Mueller, T. D. %A Hedrich, R. %D 2015 %J Mol Plant %R 10.1016/j.molp.2015.09.017 %T Venus Flytrap HKT1-Type Channel Provides for Prey Sodium Uptake into Carnivorous Plant Without Conflicting with Electrical Excitability %U http://www.ncbi.nlm.nih.gov/pubmed/26455461
• Mottershead, D.G., Sugimura, S., Al-Musawi, S.L., Li, J.J., Richani, D., White, M.A., Martin, G.A., Trotta, A.P., Ritter, L.J., Shi, J., Mueller, T.D., Harrison, C.A., and Gilchrist, R.B. (2015) ‘Cumulin, an Oocyte-secreted Heterodimer of the Transforming Growth Factor-beta Family, Is a Potent Activator of Granulosa Cells and Improves Oocyte Quality’, J Biol Chem, 290(39), 24007–20, available: https://doi.org/10.1074/jbc.M115.671487.
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  @article{mottershead2015cumulin, author = {Mottershead, D. G. and Sugimura, S. and Al-Musawi, S. L. and Li, J. J. and Richani, D. and White, M. A. and Martin, G. A. and Trotta, A. P. and Ritter, L. J. and Shi, J. and Mueller, T. D. and Harrison, C. A. and Gilchrist, R. B.}, journal = {J Biol Chem}, keywords = {imported}, number = 39, pages = {24007-20}, title = {Cumulin, an Oocyte-secreted Heterodimer of the Transforming Growth Factor-beta Family, Is a Potent Activator of Granulosa Cells and Improves Oocyte Quality}, type = {Journal Article}, volume = 290, year = 2015 }

  %0 Journal Article %1 mottershead2015cumulin %A Mottershead, D. G. %A Sugimura, S. %A Al-Musawi, S. L. %A Li, J. J. %A Richani, D. %A White, M. A. %A Martin, G. A. %A Trotta, A. P. %A Ritter, L. J. %A Shi, J. %A Mueller, T. D. %A Harrison, C. A. %A Gilchrist, R. B. %D 2015 %J J Biol Chem %N 39 %P 24007-20 %R 10.1074/jbc.M115.671487 %T Cumulin, an Oocyte-secreted Heterodimer of the Transforming Growth Factor-beta Family, Is a Potent Activator of Granulosa Cells and Improves Oocyte Quality %U http://www.ncbi.nlm.nih.gov/pubmed/26254468 %V 290
• Boschert, V., Muth, E.M., Knappik, A., Frisch, C., and Mueller, T.D. (2015) ‘Crystallization and preliminary X-ray crystallographic analysis of the sclerostin-neutralizing Fab AbD09097’, Acta Crystallogr F Struct Biol Commun, 71(Pt 4), 388–92, available: https://doi.org/10.1107/S2053230X1500360X.
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  @article{boschert2015crystallization, author = {Boschert, V. and Muth, E. M. and Knappik, A. and Frisch, C. and Mueller, T. D.}, journal = {Acta Crystallogr F Struct Biol Commun}, keywords = {imported}, number = {Pt 4}, pages = {388-92}, title = {Crystallization and preliminary X-ray crystallographic analysis of the sclerostin-neutralizing Fab AbD09097}, type = {Journal Article}, volume = 71, year = 2015 }

  %0 Journal Article %1 boschert2015crystallization %A Boschert, V. %A Muth, E. M. %A Knappik, A. %A Frisch, C. %A Mueller, T. D. %D 2015 %J Acta Crystallogr F Struct Biol Commun %N Pt 4 %P 388-92 %R 10.1107/S2053230X1500360X %T Crystallization and preliminary X-ray crystallographic analysis of the sclerostin-neutralizing Fab AbD09097 %U http://www.ncbi.nlm.nih.gov/pubmed/25849496 %V 71
• Klammert, U., Mueller, T.D., Hellmann, T.V., Wuerzler, K.K., Kotzsch, A., Schliermann, A., Schmitz, W., Kuebler, A.C., Sebald, W., and Nickel, J. (2015) ‘GDF-5 can act as a context-dependent BMP-2 antagonist’, BMC Biol, 13, 77, available: https://doi.org/10.1186/s12915-015-0183-8.
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  @article{klammert2015contextdependent, author = {Klammert, U. and Mueller, T. D. and Hellmann, T. V. and Wuerzler, K. K. and Kotzsch, A. and Schliermann, A. and Schmitz, W. and Kuebler, A. C. and Sebald, W. and Nickel, J.}, journal = {BMC Biol}, keywords = {tdmueller}, pages = 77, title = {GDF-5 can act as a context-dependent BMP-2 antagonist}, type = {Journal Article}, volume = 13, year = 2015 }

  %0 Journal Article %1 klammert2015contextdependent %A Klammert, U. %A Mueller, T. D. %A Hellmann, T. V. %A Wuerzler, K. K. %A Kotzsch, A. %A Schliermann, A. %A Schmitz, W. %A Kuebler, A. C. %A Sebald, W. %A Nickel, J. %D 2015 %J BMC Biol %P 77 %R 10.1186/s12915-015-0183-8 %T GDF-5 can act as a context-dependent BMP-2 antagonist %U http://www.ncbi.nlm.nih.gov/pubmed/26385096 %V 13
• Stange, K., Desir, J., Kakar, N., Mueller, T.D., Budde, B.S., Gordon, C.T., Horn, D., Seemann, P., and Borck, G. (2015) ‘A hypomorphic BMPR1B mutation causes du Pan acromesomelic dysplasia’, Orphanet J Rare Dis, 10, 84, available: https://doi.org/10.1186/s13023-015-0299-5.
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  @article{stange2015hypomorphic, author = {Stange, K. and Desir, J. and Kakar, N. and Mueller, T. D. and Budde, B. S. and Gordon, C. T. and Horn, D. and Seemann, P. and Borck, G.}, journal = {Orphanet J Rare Dis}, keywords = {tdmueller}, pages = 84, title = {A hypomorphic BMPR1B mutation causes du Pan acromesomelic dysplasia}, type = {Journal Article}, volume = 10, year = 2015 }

  %0 Journal Article %1 stange2015hypomorphic %A Stange, K. %A Desir, J. %A Kakar, N. %A Mueller, T. D. %A Budde, B. S. %A Gordon, C. T. %A Horn, D. %A Seemann, P. %A Borck, G. %D 2015 %J Orphanet J Rare Dis %P 84 %R 10.1186/s13023-015-0299-5 %T A hypomorphic BMPR1B mutation causes du Pan acromesomelic dysplasia %U http://www.ncbi.nlm.nih.gov/pubmed/26105076 %V 10

• Maierhofer, T., Lind, C., Huttl, S., Scherzer, S., Papenfuss, M., Simon, J., Al-Rasheid, K.A., Ache, P., Rennenberg, H., Hedrich, R., Muller, T.D., and Geiger, D. (2014) ‘A Single-Pore Residue Renders the Arabidopsis Root Anion Channel SLAH2 Highly Nitrate Selective’, Plant Cell, 26(6), 2554–2567, available: https://doi.org/10.1105/tpc.114.125849.
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  @article{maierhofer2014singlepore, author = {Maierhofer, T. and Lind, C. and Huttl, S. and Scherzer, S. and Papenfuss, M. and Simon, J. and Al-Rasheid, K. A. and Ache, P. and Rennenberg, H. and Hedrich, R. and Muller, T. D. and Geiger, D.}, journal = {Plant Cell}, keywords = {imported}, number = 6, pages = {2554-2567}, title = {A Single-Pore Residue Renders the Arabidopsis Root Anion Channel SLAH2 Highly Nitrate Selective}, type = {Journal Article}, volume = 26, year = 2014 }

  %0 Journal Article %1 maierhofer2014singlepore %A Maierhofer, T. %A Lind, C. %A Huttl, S. %A Scherzer, S. %A Papenfuss, M. %A Simon, J. %A Al-Rasheid, K. A. %A Ache, P. %A Rennenberg, H. %A Hedrich, R. %A Muller, T. D. %A Geiger, D. %D 2014 %J Plant Cell %N 6 %P 2554-2567 %R 10.1105/tpc.114.125849 %T A Single-Pore Residue Renders the Arabidopsis Root Anion Channel SLAH2 Highly Nitrate Selective %U http://www.ncbi.nlm.nih.gov/pubmed/24938289 %V 26
• Tzvetkov, M.V., Seitz, T., Bokelmann, K., Mueller, T., Brockmoller, J., and Koepsell, H. (2014) ‘Does the haplotype Met408-Del420, which was apparently predictive for imatinib efficacy, really exist and how strongly may it affect OCT1 activity?’, Blood, 123(9), 1427–9, available: https://doi.org/10.1182/blood-2013-11-535864.
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  @article{tzvetkov2014haplotype, author = {Tzvetkov, M. V. and Seitz, T. and Bokelmann, K. and Mueller, T. and Brockmoller, J. and Koepsell, H.}, journal = {Blood}, keywords = {imported}, number = 9, pages = {1427-9}, title = {Does the haplotype Met408-Del420, which was apparently predictive for imatinib efficacy, really exist and how strongly may it affect OCT1 activity?}, type = {Journal Article}, volume = 123, year = 2014 }

  %0 Journal Article %1 tzvetkov2014haplotype %A Tzvetkov, M. V. %A Seitz, T. %A Bokelmann, K. %A Mueller, T. %A Brockmoller, J. %A Koepsell, H. %D 2014 %J Blood %N 9 %P 1427-9 %R 10.1182/blood-2013-11-535864 %T Does the haplotype Met408-Del420, which was apparently predictive for imatinib efficacy, really exist and how strongly may it affect OCT1 activity? %U http://www.ncbi.nlm.nih.gov/pubmed/24578499 %V 123
• Duppatla, V., Gjorgjevikj, M., Schmitz, W., Hermanns, H.M., Schafer, C.M., Kottmair, M., Muller, T., and Sebald, W. (2014) ‘IL-4 analogues with site-specific chemical modification at position 121 inhibit IL-4 and IL-13 biological activities’, Bioconjugate chemistry, 25(1), 52–62, available: https://doi.org/10.1021/bc400307k.
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  @article{duppatla2014analogues, author = {Duppatla, V. and Gjorgjevikj, M. and Schmitz, W. and Hermanns, H. M. and Schafer, C. M. and Kottmair, M. and Muller, T. and Sebald, W.}, journal = {Bioconjugate chemistry}, keywords = {imported}, number = 1, pages = {52-62}, title = {IL-4 analogues with site-specific chemical modification at position 121 inhibit IL-4 and IL-13 biological activities}, type = {Journal Article}, volume = 25, year = 2014 }

  %0 Journal Article %1 duppatla2014analogues %A Duppatla, V. %A Gjorgjevikj, M. %A Schmitz, W. %A Hermanns, H. M. %A Schafer, C. M. %A Kottmair, M. %A Muller, T. %A Sebald, W. %D 2014 %J Bioconjugate chemistry %N 1 %P 52-62 %R 10.1021/bc400307k %T IL-4 analogues with site-specific chemical modification at position 121 inhibit IL-4 and IL-13 biological activities %U http://www.ncbi.nlm.nih.gov/pubmed/24341642 %V 25
• Graul-Neumann, L.M., Deichsel, A., Wille, U., Kakar, N., Koll, R., Bassir, C., Ahmad, J., Cormier-Daire, V., Mundlos, S., Kubisch, C., Borck, G., Klopocki, E., Mueller, T.D., Doelken, S.C., and Seemann, P. (2014) ‘Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe’, European journal of human genetics : EJHG, 22(6), 726–33, available: https://doi.org/10.1038/ejhg.2013.222.
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  @article{graulneumann2014homozygous, author = {Graul-Neumann, L. M. and Deichsel, A. and Wille, U. and Kakar, N. and Koll, R. and Bassir, C. and Ahmad, J. and Cormier-Daire, V. and Mundlos, S. and Kubisch, C. and Borck, G. and Klopocki, E. and Mueller, T. D. and Doelken, S. C. and Seemann, P.}, journal = {European journal of human genetics : EJHG}, keywords = {tdmueller}, number = 6, pages = {726-33}, title = {Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe}, type = {Journal Article}, volume = 22, year = 2014 }

  %0 Journal Article %1 graulneumann2014homozygous %A Graul-Neumann, L. M. %A Deichsel, A. %A Wille, U. %A Kakar, N. %A Koll, R. %A Bassir, C. %A Ahmad, J. %A Cormier-Daire, V. %A Mundlos, S. %A Kubisch, C. %A Borck, G. %A Klopocki, E. %A Mueller, T. D. %A Doelken, S. C. %A Seemann, P. %D 2014 %J European journal of human genetics : EJHG %N 6 %P 726-33 %R 10.1038/ejhg.2013.222 %T Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe %U http://www.ncbi.nlm.nih.gov/pubmed/24129431 %V 22

• Fiebig, J.E., Weidauer, S.E., Qiu, L.Y., Bauer, M., Schmieder, P., Beerbaum, M., Zhang, J.L., Oschkinat, H., Sebald, W., and Mueller, T.D. (2013) ‘The clip-segment of the von Willebrand domain 1 of the BMP modulator protein Crossveinless 2 is preformed’, Molecules, 18(10), 11658–82, available: https://doi.org/10.3390/molecules181011658.
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  @article{fiebig2013clipsegment, author = {Fiebig, J. E. and Weidauer, S. E. and Qiu, L. Y. and Bauer, M. and Schmieder, P. and Beerbaum, M. and Zhang, J. L. and Oschkinat, H. and Sebald, W. and Mueller, T. D.}, journal = {Molecules}, keywords = {imported}, number = 10, pages = {11658-82}, title = {The clip-segment of the von Willebrand domain 1 of the BMP modulator protein Crossveinless 2 is preformed}, type = {Journal Article}, volume = 18, year = 2013 }

  %0 Journal Article %1 fiebig2013clipsegment %A Fiebig, J. E. %A Weidauer, S. E. %A Qiu, L. Y. %A Bauer, M. %A Schmieder, P. %A Beerbaum, M. %A Zhang, J. L. %A Oschkinat, H. %A Sebald, W. %A Mueller, T. D. %D 2013 %J Molecules %N 10 %P 11658-82 %R 10.3390/molecules181011658 %T The clip-segment of the von Willebrand domain 1 of the BMP modulator protein Crossveinless 2 is preformed %U http://www.ncbi.nlm.nih.gov/pubmed/24071977 %V 18
• Nolte, T., Zadeh-Khorasani, M., Safarov, O., Rueff, F., Varga, R., Herbach, N., Wanke, R., Wollenberg, A., Mueller, T., Gropp, R., Wolf, E., and Siebeck, M. (2013) ‘Induction of oxazolone-mediated features of atopic dermatitis in NOD-scid IL2Rgamma(null) mice engrafted with human peripheral blood mononuclear cells’, Disease models & mechanisms, 6(1), 125–34, available: https://doi.org/10.1242/dmm.009167.
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  @article{nolte2013induction, author = {Nolte, T. and Zadeh-Khorasani, M. and Safarov, O. and Rueff, F. and Varga, R. and Herbach, N. and Wanke, R. and Wollenberg, A. and Mueller, T. and Gropp, R. and Wolf, E. and Siebeck, M.}, journal = {Disease models & mechanisms}, keywords = {imported}, number = 1, pages = {125-34}, title = {Induction of oxazolone-mediated features of atopic dermatitis in NOD-scid IL2Rgamma(null) mice engrafted with human peripheral blood mononuclear cells}, type = {Journal Article}, volume = 6, year = 2013 }

  %0 Journal Article %1 nolte2013induction %A Nolte, T. %A Zadeh-Khorasani, M. %A Safarov, O. %A Rueff, F. %A Varga, R. %A Herbach, N. %A Wanke, R. %A Wollenberg, A. %A Mueller, T. %A Gropp, R. %A Wolf, E. %A Siebeck, M. %D 2013 %J Disease models & mechanisms %N 1 %P 125-34 %R 10.1242/dmm.009167 %T Induction of oxazolone-mediated features of atopic dermatitis in NOD-scid IL2Rgamma(null) mice engrafted with human peripheral blood mononuclear cells %U http://www.ncbi.nlm.nih.gov/pubmed/22822046 %V 6
• Diestel, U., Resch, M., Meinhardt, K., Weiler, S., Hellmann, T.V., Mueller, T.D., Nickel, J., Eichler, J., and Muller, Y.A. (2013) ‘Identification of a Novel TGF-beta-Binding Site in the Zona Pellucida C-terminal (ZP-C) Domain of TGF-beta-Receptor-3 (TGFR-3)’, PLoS One, 8(6), e67214, available: https://doi.org/10.1371/journal.pone.0067214.
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  @article{diestel2013identification, author = {Diestel, U. and Resch, M. and Meinhardt, K. and Weiler, S. and Hellmann, T. V. and Mueller, T. D. and Nickel, J. and Eichler, J. and Muller, Y. A.}, journal = {PLoS One}, keywords = {imported}, number = 6, pages = {e67214}, title = {Identification of a Novel TGF-beta-Binding Site in the Zona Pellucida C-terminal (ZP-C) Domain of TGF-beta-Receptor-3 (TGFR-3)}, type = {Journal Article}, volume = 8, year = 2013 }

  %0 Journal Article %1 diestel2013identification %A Diestel, U. %A Resch, M. %A Meinhardt, K. %A Weiler, S. %A Hellmann, T. V. %A Mueller, T. D. %A Nickel, J. %A Eichler, J. %A Muller, Y. A. %D 2013 %J PLoS One %N 6 %P e67214 %R 10.1371/journal.pone.0067214 %T Identification of a Novel TGF-beta-Binding Site in the Zona Pellucida C-terminal (ZP-C) Domain of TGF-beta-Receptor-3 (TGFR-3) %U http://www.ncbi.nlm.nih.gov/pubmed/23826237 %V 8
• Nolte, T., Zadeh-Khorasani, M., Safarov, O., Rueff, F., Gulberg, V., Herbach, N., Wollenberg, A., Mueller, T., Siebeck, M., Wolf, E., and Gropp, R. (2013) ‘Oxazolone and ethanol induce colitis in non-obese diabetic-severe combined immunodeficiency interleukin-2Rgamma(null) mice engrafted with human peripheral blood mononuclear cells’, Clinical and experimental immunology, 172(2), 349–62, available: https://doi.org/10.1111/cei.12057.
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  @article{nolte2013oxazolone, author = {Nolte, T. and Zadeh-Khorasani, M. and Safarov, O. and Rueff, F. and Gulberg, V. and Herbach, N. and Wollenberg, A. and Mueller, T. and Siebeck, M. and Wolf, E. and Gropp, R.}, journal = {Clinical and experimental immunology}, keywords = {imported}, number = 2, pages = {349-62}, title = {Oxazolone and ethanol induce colitis in non-obese diabetic-severe combined immunodeficiency interleukin-2Rgamma(null) mice engrafted with human peripheral blood mononuclear cells}, type = {Journal Article}, volume = 172, year = 2013 }

  %0 Journal Article %1 nolte2013oxazolone %A Nolte, T. %A Zadeh-Khorasani, M. %A Safarov, O. %A Rueff, F. %A Gulberg, V. %A Herbach, N. %A Wollenberg, A. %A Mueller, T. %A Siebeck, M. %A Wolf, E. %A Gropp, R. %D 2013 %J Clinical and experimental immunology %N 2 %P 349-62 %R 10.1111/cei.12057 %T Oxazolone and ethanol induce colitis in non-obese diabetic-severe combined immunodeficiency interleukin-2Rgamma(null) mice engrafted with human peripheral blood mononuclear cells %U http://www.ncbi.nlm.nih.gov/pubmed/23574330 %V 172
• Laisney, J.A., Mueller, T.D., Schartl, M., and Meierjohann, S. (2013) ‘Hyperactivation of constitutively dimerized oncogenic EGF receptors by autocrine loops’, Oncogene, 32(19), 2403–11, available: https://doi.org/10.1038/onc.2012.267.
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  @article{laisney2013hyperactivation, author = {Laisney, J. A. and Mueller, T. D. and Schartl, M. and Meierjohann, S.}, journal = {Oncogene}, keywords = {imported}, number = 19, pages = {2403-11}, title = {Hyperactivation of constitutively dimerized oncogenic EGF receptors by autocrine loops}, type = {Journal Article}, volume = 32, year = 2013 }

  %0 Journal Article %1 laisney2013hyperactivation %A Laisney, J. A. %A Mueller, T. D. %A Schartl, M. %A Meierjohann, S. %D 2013 %J Oncogene %N 19 %P 2403-11 %R 10.1038/onc.2012.267 %T Hyperactivation of constitutively dimerized oncogenic EGF receptors by autocrine loops %U http://www.ncbi.nlm.nih.gov/pubmed/22751127 %V 32
• Boschert, V., van Dinther, M., Weidauer, S., van Pee, K., Muth, E.M., Ten Dijke, P., and Mueller, T.D. (2013) ‘Mutational analysis of sclerostin shows importance of the flexible loop and the cystine-knot for wnt-signaling inhibition’, PLoS One, 8(11), e81710, available: https://doi.org/10.1371/journal.pone.0081710.
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  @article{boschert2013mutational, author = {Boschert, V. and van Dinther, M. and Weidauer, S. and van Pee, K. and Muth, E. M. and Ten Dijke, P. and Mueller, T. D.}, journal = {PLoS One}, keywords = {imported}, number = 11, pages = {e81710}, title = {Mutational analysis of sclerostin shows importance of the flexible loop and the cystine-knot for wnt-signaling inhibition}, type = {Journal Article}, volume = 8, year = 2013 }

  %0 Journal Article %1 boschert2013mutational %A Boschert, V. %A van Dinther, M. %A Weidauer, S. %A van Pee, K. %A Muth, E. M. %A Ten Dijke, P. %A Mueller, T. D. %D 2013 %J PLoS One %N 11 %P e81710 %R 10.1371/journal.pone.0081710 %T Mutational analysis of sclerostin shows importance of the flexible loop and the cystine-knot for wnt-signaling inhibition %U http://www.ncbi.nlm.nih.gov/pubmed/24312339 %V 8
• Mottershead, D.G., Harrison, C.A., Mueller, T.D., Stanton, P.G., Gilchrist, R.B., and McNatty, K.P. (2013) ‘Growth differentiation factor 9:bone morphogenetic protein 15 (GDF9:BMP15) synergism and protein heterodimerization’, Proceedings of the National Academy of Sciences of the United States of America, 110(25), E2257, available: https://doi.org/10.1073/pnas.1303459110.
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  @article{mottershead2013growth, author = {Mottershead, D. G. and Harrison, C. A. and Mueller, T. D. and Stanton, P. G. and Gilchrist, R. B. and McNatty, K. P.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, keywords = {imported}, number = 25, pages = {E2257}, title = {Growth differentiation factor 9:bone morphogenetic protein 15 (GDF9:BMP15) synergism and protein heterodimerization}, type = {Journal Article}, volume = 110, year = 2013 }

  %0 Journal Article %1 mottershead2013growth %A Mottershead, D. G. %A Harrison, C. A. %A Mueller, T. D. %A Stanton, P. G. %A Gilchrist, R. B. %A McNatty, K. P. %D 2013 %J Proceedings of the National Academy of Sciences of the United States of America %N 25 %P E2257 %R 10.1073/pnas.1303459110 %T Growth differentiation factor 9:bone morphogenetic protein 15 (GDF9:BMP15) synergism and protein heterodimerization %U http://www.ncbi.nlm.nih.gov/pubmed/23650403 %V 110
• van Dinther, M., Zhang, J., Weidauer, S.E., Boschert, V., Muth, E.M., Knappik, A., de Gorter, D.J., van Kasteren, P.B., Frisch, C., Mueller, T.D., and Ten Dijke, P. (2013) ‘Anti-Sclerostin Antibody Inhibits Internalization of Sclerostin and Sclerostin-Mediated Antagonism of Wnt/LRP6 Signaling’, PLoS One, 8(4), e62295, available: https://doi.org/10.1371/journal.pone.0062295.
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  @article{vandinther2013antisclerostin, author = {van Dinther, M. and Zhang, J. and Weidauer, S. E. and Boschert, V. and Muth, E. M. and Knappik, A. and de Gorter, D. J. and van Kasteren, P. B. and Frisch, C. and Mueller, T. D. and Ten Dijke, P.}, journal = {PLoS One}, keywords = {tdmueller}, number = 4, pages = {e62295}, title = {Anti-Sclerostin Antibody Inhibits Internalization of Sclerostin and Sclerostin-Mediated Antagonism of Wnt/LRP6 Signaling}, type = {Journal Article}, volume = 8, year = 2013 }

  %0 Journal Article %1 vandinther2013antisclerostin %A van Dinther, M. %A Zhang, J. %A Weidauer, S. E. %A Boschert, V. %A Muth, E. M. %A Knappik, A. %A de Gorter, D. J. %A van Kasteren, P. B. %A Frisch, C. %A Mueller, T. D. %A Ten Dijke, P. %D 2013 %J PLoS One %N 4 %P e62295 %R 10.1371/journal.pone.0062295 %T Anti-Sclerostin Antibody Inhibits Internalization of Sclerostin and Sclerostin-Mediated Antagonism of Wnt/LRP6 Signaling %U http://www.ncbi.nlm.nih.gov/pubmed/23638027 %V 8
• Zadeh-Khorasani, M., Nolte, T., Mueller, T.D., Pechlivanis, M., Rueff, F., Wollenberg, A., Fricker, G., Wolf, E., Siebeck, M., and Gropp, R. (2013) ‘NOD-scid IL2R gammanull mice engrafted with human peripheral blood mononuclear cells as a model to test therapeutics targeting human signaling pathways’, Journal of translational medicine, 11, 4, available: https://doi.org/10.1186/1479-5876-11-4.
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  @article{zadehkhorasani2013nodscid, author = {Zadeh-Khorasani, M. and Nolte, T. and Mueller, T. D. and Pechlivanis, M. and Rueff, F. and Wollenberg, A. and Fricker, G. and Wolf, E. and Siebeck, M. and Gropp, R.}, journal = {Journal of translational medicine}, keywords = {imported}, pages = 4, title = {NOD-scid IL2R gammanull mice engrafted with human peripheral blood mononuclear cells as a model to test therapeutics targeting human signaling pathways}, type = {Journal Article}, volume = 11, year = 2013 }

  %0 Journal Article %1 zadehkhorasani2013nodscid %A Zadeh-Khorasani, M. %A Nolte, T. %A Mueller, T. D. %A Pechlivanis, M. %A Rueff, F. %A Wollenberg, A. %A Fricker, G. %A Wolf, E. %A Siebeck, M. %A Gropp, R. %D 2013 %J Journal of translational medicine %P 4 %R 10.1186/1479-5876-11-4 %T NOD-scid IL2R gammanull mice engrafted with human peripheral blood mononuclear cells as a model to test therapeutics targeting human signaling pathways %U http://www.ncbi.nlm.nih.gov/pubmed/23294516 %V 11
• Sibilski, C., Mueller, T., Kollipara, L., Zahedi, R.P., Rapp, U.R., Rudel, T., and Baljuls, A. (2013) ‘Tyr728 in the kinase domain of the murine kinase suppressor of RAS 1 regulates binding and activation of the mitogen-activated protein kinase kinase’, The Journal of biological chemistry, 288(49), 35237–52, available: https://doi.org/10.1074/jbc.M113.490235.
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  @article{sibilski2013tyr728, author = {Sibilski, C. and Mueller, T. and Kollipara, L. and Zahedi, R. P. and Rapp, U. R. and Rudel, T. and Baljuls, A.}, journal = {The Journal of biological chemistry}, keywords = {tdmueller}, number = 49, pages = {35237-52}, title = {Tyr728 in the kinase domain of the murine kinase suppressor of RAS 1 regulates binding and activation of the mitogen-activated protein kinase kinase}, type = {Journal Article}, volume = 288, year = 2013 }

  %0 Journal Article %1 sibilski2013tyr728 %A Sibilski, C. %A Mueller, T. %A Kollipara, L. %A Zahedi, R. P. %A Rapp, U. R. %A Rudel, T. %A Baljuls, A. %D 2013 %J The Journal of biological chemistry %N 49 %P 35237-52 %R 10.1074/jbc.M113.490235 %T Tyr728 in the kinase domain of the murine kinase suppressor of RAS 1 regulates binding and activation of the mitogen-activated protein kinase kinase %U http://www.ncbi.nlm.nih.gov/pubmed/24158441 %V 288
• Hannema, S.E., van Duyvenvoorde, H.A., Premsler, T., Yang, R.B., Mueller, T.D., Gassner, B., Oberwinkler, H., Roelfsema, F., Santen, G.W., Prickett, T., Kant, S.G., Verkerk, A.J., Uitterlinden, A.G., Espiner, E., Ruivenkamp, C.A., Oostdijk, W., Pereira, A.M., Losekoot, M., Kuhn, M., and Wit, J.M. (2013) ‘An activating mutation in the kinase homology domain of the natriuretic peptide receptor-2 causes extremely tall stature without skeletal deformities’, The Journal of clinical endocrinology and metabolism, 98(12), E1988–98, available: https://doi.org/10.1210/jc.2013-2358.
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  @article{hannema2013activating, author = {Hannema, S. E. and van Duyvenvoorde, H. A. and Premsler, T. and Yang, R. B. and Mueller, T. D. and Gassner, B. and Oberwinkler, H. and Roelfsema, F. and Santen, G. W. and Prickett, T. and Kant, S. G. and Verkerk, A. J. and Uitterlinden, A. G. and Espiner, E. and Ruivenkamp, C. A. and Oostdijk, W. and Pereira, A. M. and Losekoot, M. and Kuhn, M. and Wit, J. M.}, journal = {The Journal of clinical endocrinology and metabolism}, keywords = {imported}, number = 12, pages = {E1988-98}, title = {An activating mutation in the kinase homology domain of the natriuretic peptide receptor-2 causes extremely tall stature without skeletal deformities}, type = {Journal Article}, volume = 98, year = 2013 }

  %0 Journal Article %1 hannema2013activating %A Hannema, S. E. %A van Duyvenvoorde, H. A. %A Premsler, T. %A Yang, R. B. %A Mueller, T. D. %A Gassner, B. %A Oberwinkler, H. %A Roelfsema, F. %A Santen, G. W. %A Prickett, T. %A Kant, S. G. %A Verkerk, A. J. %A Uitterlinden, A. G. %A Espiner, E. %A Ruivenkamp, C. A. %A Oostdijk, W. %A Pereira, A. M. %A Losekoot, M. %A Kuhn, M. %A Wit, J. M. %D 2013 %J The Journal of clinical endocrinology and metabolism %N 12 %P E1988-98 %R 10.1210/jc.2013-2358 %T An activating mutation in the kinase homology domain of the natriuretic peptide receptor-2 causes extremely tall stature without skeletal deformities %U http://www.ncbi.nlm.nih.gov/pubmed/24057292 %V 98
• Scherzer, S., Krol, E., Kreuzer, I., Kruse, J., Karl, F., von Ruden, M., Escalante-Perez, M., Muller, T., Rennenberg, H., Al-Rasheid, K.A., Neher, E., and Hedrich, R. (2013) ‘The Dionaea muscipula Ammonium Channel DmAMT1 Provides NH4(+) Uptake Associated with Venus Flytrap’s Prey Digestion’, Current biology : CB, 23(17), 1649–57, available: https://doi.org/10.1016/j.cub.2013.07.028.
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  @article{scherzer2013dionaea, author = {Scherzer, S. and Krol, E. and Kreuzer, I. and Kruse, J. and Karl, F. and von Ruden, M. and Escalante-Perez, M. and Muller, T. and Rennenberg, H. and Al-Rasheid, K. A. and Neher, E. and Hedrich, R.}, journal = {Current biology : CB}, keywords = {imported}, number = 17, pages = {1649-57}, title = {The Dionaea muscipula Ammonium Channel DmAMT1 Provides NH4(+) Uptake Associated with Venus Flytrap's Prey Digestion}, type = {Journal Article}, volume = 23, year = 2013 }

  %0 Journal Article %1 scherzer2013dionaea %A Scherzer, S. %A Krol, E. %A Kreuzer, I. %A Kruse, J. %A Karl, F. %A von Ruden, M. %A Escalante-Perez, M. %A Muller, T. %A Rennenberg, H. %A Al-Rasheid, K. A. %A Neher, E. %A Hedrich, R. %D 2013 %J Current biology : CB %N 17 %P 1649-57 %R 10.1016/j.cub.2013.07.028 %T The Dionaea muscipula Ammonium Channel DmAMT1 Provides NH4(+) Uptake Associated with Venus Flytrap's Prey Digestion %U http://www.ncbi.nlm.nih.gov/pubmed/23954430 %V 23
• Whitman, M., Rosen, V., Brivanlou, A.H., Groppe, J.C., Sebald, W., and Mueller, T. (2013) ‘Regarding the mechanism of action of a proposed peptide agonist of the bone morphogenetic protein receptor activin-like kinase 3’, Nature medicine, 19(7), 809–10, available: https://doi.org/10.1038/nm.3080.
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  @article{whitman2013regarding, author = {Whitman, M. and Rosen, V. and Brivanlou, A. H. and Groppe, J. C. and Sebald, W. and Mueller, T.}, journal = {Nature medicine}, keywords = {imported}, number = 7, pages = {809-10}, title = {Regarding the mechanism of action of a proposed peptide agonist of the bone morphogenetic protein receptor activin-like kinase 3}, type = {Journal Article}, volume = 19, year = 2013 }

  %0 Journal Article %1 whitman2013regarding %A Whitman, M. %A Rosen, V. %A Brivanlou, A. H. %A Groppe, J. C. %A Sebald, W. %A Mueller, T. %D 2013 %J Nature medicine %N 7 %P 809-10 %R 10.1038/nm.3080 %T Regarding the mechanism of action of a proposed peptide agonist of the bone morphogenetic protein receptor activin-like kinase 3 %U http://www.ncbi.nlm.nih.gov/pubmed/23836213 %V 19

• Froese, A., Breher, S.S., Waldeyer, C., Schindler, R.F., Nikolaev, V.O., Rinne, S., Wischmeyer, E., Schlueter, J., Becher, J., Simrick, S., Vauti, F., Kuhtz, J., Meister, P., Kreissl, S., Torlopp, A., Liebig, S.K., Laakmann, S., Muller, T.D., Neumann, J., Stieber, J., Ludwig, A., Maier, S.K., Decher, N., Arnold, H.H., Kirchhof, P., Fabritz, L., and Brand, T. (2012) ‘Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice’, J Clin Invest, 122(3), 1119–30, available: https://doi.org/10.1172/JCI59410.
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  @article{froese2012popeye, author = {Froese, A. and Breher, S. S. and Waldeyer, C. and Schindler, R. F. and Nikolaev, V. O. and Rinne, S. and Wischmeyer, E. and Schlueter, J. and Becher, J. and Simrick, S. and Vauti, F. and Kuhtz, J. and Meister, P. and Kreissl, S. and Torlopp, A. and Liebig, S. K. and Laakmann, S. and Muller, T. D. and Neumann, J. and Stieber, J. and Ludwig, A. and Maier, S. K. and Decher, N. and Arnold, H. H. and Kirchhof, P. and Fabritz, L. and Brand, T.}, journal = {J Clin Invest}, keywords = {imported}, number = 3, pages = {1119-30}, title = {Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice}, type = {Journal Article}, volume = 122, year = 2012 }

  %0 Journal Article %1 froese2012popeye %A Froese, A. %A Breher, S. S. %A Waldeyer, C. %A Schindler, R. F. %A Nikolaev, V. O. %A Rinne, S. %A Wischmeyer, E. %A Schlueter, J. %A Becher, J. %A Simrick, S. %A Vauti, F. %A Kuhtz, J. %A Meister, P. %A Kreissl, S. %A Torlopp, A. %A Liebig, S. K. %A Laakmann, S. %A Muller, T. D. %A Neumann, J. %A Stieber, J. %A Ludwig, A. %A Maier, S. K. %A Decher, N. %A Arnold, H. H. %A Kirchhof, P. %A Fabritz, L. %A Brand, T. %D 2012 %J J Clin Invest %N 3 %P 1119-30 %R 10.1172/JCI59410 %T Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice %U http://www.ncbi.nlm.nih.gov/pubmed/22354168 %V 122
• Hellmann, T., Nickel, J., and Mueller, T. (2012) ‘Missense mutations in GDF5 signaling: molecular mechanisms behind skeletal malformation’, in Cooper, D. and Chen, J.-M., eds., Gene Mutation, Rijeka, Croatia: InTech.
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  @inbook{hellmann2012missense, address = {Rijeka, Croatia}, author = {Hellmann, T.V. and Nickel, J. and Mueller, T.D.}, booktitle = {Gene Mutation}, editor = {Cooper, D. and Chen, J.-M.}, keywords = {imported}, publisher = {InTech}, title = {Missense mutations in GDF5 signaling: molecular mechanisms behind skeletal malformation}, type = {Book Section}, year = 2012 }

  %0 Book Section %1 hellmann2012missense %A Hellmann, T.V. %A Nickel, J. %A Mueller, T.D. %B Gene Mutation %C Rijeka, Croatia %D 2012 %E Cooper, D. %E Chen, J.-M. %I InTech %T Missense mutations in GDF5 signaling: molecular mechanisms behind skeletal malformation %@ 980-953-307-125-6
• Schwaerzer, G.K., Hiepen, C., Schrewe, H., Nickel, J., Ploeger, F., Sebald, W., Mueller, T., and Knaus, P. (2012) ‘New insights into the molecular mechanism of multiple synostoses syndrome (SYNS): Mutation within the GDF5 knuckle epitope causes noggin-resistance’, J Bone Miner Res, 27(2), 429–442, available: https://doi.org/10.1002/jbmr.532.
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  @article{schwaerzer2012insights, author = {Schwaerzer, G. K. and Hiepen, C. and Schrewe, H. and Nickel, J. and Ploeger, F. and Sebald, W. and Mueller, T. and Knaus, P.}, journal = {J Bone Miner Res}, keywords = {imported}, number = 2, pages = {429-442}, title = {New insights into the molecular mechanism of multiple synostoses syndrome (SYNS): Mutation within the GDF5 knuckle epitope causes noggin-resistance}, type = {Journal Article}, volume = 27, year = 2012 }

  %0 Journal Article %1 schwaerzer2012insights %A Schwaerzer, G. K. %A Hiepen, C. %A Schrewe, H. %A Nickel, J. %A Ploeger, F. %A Sebald, W. %A Mueller, T. %A Knaus, P. %D 2012 %J J Bone Miner Res %N 2 %P 429-442 %R 10.1002/jbmr.532 %T New insights into the molecular mechanism of multiple synostoses syndrome (SYNS): Mutation within the GDF5 knuckle epitope causes noggin-resistance %U http://www.ncbi.nlm.nih.gov/pubmed/21976273 %V 27
• Urusova, D.V., Isupov, M.N., Antonyuk, S., Kachalova, G.S., Obmolova, G., Vagin, A.A., Lebedev, A.A., Burenkov, G.P., Dauter, Z., Bartunik, H.D., Lamzin, V.S., Melik-Adamyan, W.R., Mueller, T.D., and Schnackerz, K.D. (2012) ‘Crystal structure of D-serine dehydratase from Escherichia coli’, Biochim Biophys Acta, 1824(3), 422–32, available: https://doi.org/10.1016/j.bbapap.2011.10.017.
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  @article{urusova2012crystal, author = {Urusova, D. V. and Isupov, M. N. and Antonyuk, S. and Kachalova, G. S. and Obmolova, G. and Vagin, A. A. and Lebedev, A. A. and Burenkov, G. P. and Dauter, Z. and Bartunik, H. D. and Lamzin, V. S. and Melik-Adamyan, W. R. and Mueller, T. D. and Schnackerz, K. D.}, journal = {Biochim Biophys Acta}, keywords = {imported}, number = 3, pages = {422-32}, title = {Crystal structure of D-serine dehydratase from Escherichia coli}, type = {Journal Article}, volume = 1824, year = 2012 }

  %0 Journal Article %1 urusova2012crystal %A Urusova, D. V. %A Isupov, M. N. %A Antonyuk, S. %A Kachalova, G. S. %A Obmolova, G. %A Vagin, A. A. %A Lebedev, A. A. %A Burenkov, G. P. %A Dauter, Z. %A Bartunik, H. D. %A Lamzin, V. S. %A Melik-Adamyan, W. R. %A Mueller, T. D. %A Schnackerz, K. D. %D 2012 %J Biochim Biophys Acta %N 3 %P 422-32 %R 10.1016/j.bbapap.2011.10.017 %T Crystal structure of D-serine dehydratase from Escherichia coli %U http://www.ncbi.nlm.nih.gov/pubmed/22197591 %V 1824
• Mueller, T.D. and Nickel, J. (2012) ‘Promiscuity and specificity in BMP receptor activation’, FEBS letters, 586(14), 1846–59, available: https://doi.org/10.1016/j.febslet.2012.02.043.
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  @article{mueller2012promiscuity, author = {Mueller, T. D. and Nickel, J.}, journal = {FEBS letters}, keywords = {imported}, number = 14, pages = {1846-59}, title = {Promiscuity and specificity in BMP receptor activation}, type = {Journal Article}, volume = 586, year = 2012 }

  %0 Journal Article %1 mueller2012promiscuity %A Mueller, T. D. %A Nickel, J. %D 2012 %J FEBS letters %N 14 %P 1846-59 %R 10.1016/j.febslet.2012.02.043 %T Promiscuity and specificity in BMP receptor activation %U http://www.ncbi.nlm.nih.gov/pubmed/22710174 %V 586
• Duppatla, V., Gjorgjevikj, M., Schmitz, W., Kottmair, M., Mueller, T.D., and Sebald, W. (2012) ‘Enzymatic deglutathionylation to generate interleukin-4 cysteine muteins with free thiol’, Bioconjugate chemistry, 23(7), 1396–405, available: https://doi.org/10.1021/bc2004389.
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  @article{duppatla2012enzymatic, author = {Duppatla, V. and Gjorgjevikj, M. and Schmitz, W. and Kottmair, M. and Mueller, T. D. and Sebald, W.}, journal = {Bioconjugate chemistry}, keywords = {imported}, number = 7, pages = {1396-405}, title = {Enzymatic deglutathionylation to generate interleukin-4 cysteine muteins with free thiol}, type = {Journal Article}, volume = 23, year = 2012 }

  %0 Journal Article %1 duppatla2012enzymatic %A Duppatla, V. %A Gjorgjevikj, M. %A Schmitz, W. %A Kottmair, M. %A Mueller, T. D. %A Sebald, W. %D 2012 %J Bioconjugate chemistry %N 7 %P 1396-405 %R 10.1021/bc2004389 %T Enzymatic deglutathionylation to generate interleukin-4 cysteine muteins with free thiol %U http://www.ncbi.nlm.nih.gov/pubmed/22681442 %V 23
• Back, J.W., Frisch, C., Van Pee, K., Boschert, V., van Vught, R., Puijk, W., Mueller, T.D., Knappik, A., and Timmerman, P. (2012) ‘Selecting highly structure-specific antibodies using structured synthetic mimics of the cystine knot protein sclerostin’, Protein Eng Des Sel, 25(5), 251–9, available: https://doi.org/10.1093/protein/gzs012.
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  @article{back2012selecting, author = {Back, J. W. and Frisch, C. and Van Pee, K. and Boschert, V. and van Vught, R. and Puijk, W. and Mueller, T. D. and Knappik, A. and Timmerman, P.}, journal = {Protein Eng Des Sel}, keywords = {imported}, number = 5, pages = {251-9}, title = {Selecting highly structure-specific antibodies using structured synthetic mimics of the cystine knot protein sclerostin}, type = {Journal Article}, volume = 25, year = 2012 }

  %0 Journal Article %1 back2012selecting %A Back, J. W. %A Frisch, C. %A Van Pee, K. %A Boschert, V. %A van Vught, R. %A Puijk, W. %A Mueller, T. D. %A Knappik, A. %A Timmerman, P. %D 2012 %J Protein Eng Des Sel %N 5 %P 251-9 %R 10.1093/protein/gzs012 %T Selecting highly structure-specific antibodies using structured synthetic mimics of the cystine knot protein sclerostin %U http://www.ncbi.nlm.nih.gov/pubmed/22454505 %V 25
• Latz, A., Mehlmer, N., Zapf, S., Mueller, T.D., Wurzinger, B., Pfister, B., Csaszar, E., Hedrich, R., Teige, M., and Becker, D. (2012) ‘Salt stress triggers phosphorylation of the Arabidopsis vacuolar K+ channel TPK1 by calcium dependent protein kinases (CDPKs)’, Molecular Plant, 6(4), 1274–1289, available: https://doi.org/10.1093/mp/sss158.
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  @article{latz2012stress, author = {Latz, A. and Mehlmer, N. and Zapf, S. and Mueller, T. D. and Wurzinger, B. and Pfister, B. and Csaszar, E. and Hedrich, R. and Teige, M. and Becker, D.}, journal = {Molecular Plant}, keywords = {tdmueller}, number = 4, pages = {1274-1289}, title = {Salt stress triggers phosphorylation of the Arabidopsis vacuolar K+ channel TPK1 by calcium dependent protein kinases (CDPKs)}, type = {Journal Article}, volume = 6, year = 2012 }

  %0 Journal Article %1 latz2012stress %A Latz, A. %A Mehlmer, N. %A Zapf, S. %A Mueller, T. D. %A Wurzinger, B. %A Pfister, B. %A Csaszar, E. %A Hedrich, R. %A Teige, M. %A Becker, D. %D 2012 %J Molecular Plant %N 4 %P 1274-1289 %R 10.1093/mp/sss158 %T Salt stress triggers phosphorylation of the Arabidopsis vacuolar K+ channel TPK1 by calcium dependent protein kinases (CDPKs) %U http://www.ncbi.nlm.nih.gov/pubmed/23253603 %V 6
• Egenberger, B., Gorboulev, V., Keller, T., Gorbunov, D., Gottlieb, N., Geiger, D., Mueller, T.D., and Koepsell, H. (2012) ‘A substrate binding hinge domain is critical for transport-related structural changes of organic cation transporter 1’, J Biol Chem, 287(37), 31561–73, available: https://doi.org/10.1074/jbc.M112.388793.
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  @article{egenberger2012substrate, author = {Egenberger, B. and Gorboulev, V. and Keller, T. and Gorbunov, D. and Gottlieb, N. and Geiger, D. and Mueller, T. D. and Koepsell, H.}, journal = {J Biol Chem}, keywords = {imported}, number = 37, pages = {31561-73}, title = {A substrate binding hinge domain is critical for transport-related structural changes of organic cation transporter 1}, type = {Journal Article}, volume = 287, year = 2012 }

  %0 Journal Article %1 egenberger2012substrate %A Egenberger, B. %A Gorboulev, V. %A Keller, T. %A Gorbunov, D. %A Gottlieb, N. %A Geiger, D. %A Mueller, T. D. %A Koepsell, H. %D 2012 %J J Biol Chem %N 37 %P 31561-73 %R 10.1074/jbc.M112.388793 %T A substrate binding hinge domain is critical for transport-related structural changes of organic cation transporter 1 %U http://www.ncbi.nlm.nih.gov/pubmed/22810231 %V 287

• Patino, E., Kotzsch, A., Saremba, S., Nickel, J., Schmitz, W., Sebald, W., and Mueller, T.D. (2011) ‘Structure Analysis of the IL-5 Ligand-Receptor Complex Reveals a Wrench-like Architecture for IL-5Ralpha’, Structure, 19(12), 1864–75, available: https://doi.org/10.1016/j.str.2011.08.015.
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  @article{patino2011structure, author = {Patino, E. and Kotzsch, A. and Saremba, S. and Nickel, J. and Schmitz, W. and Sebald, W. and Mueller, T. D.}, journal = {Structure}, keywords = {imported}, number = 12, pages = {1864-75}, title = {Structure Analysis of the IL-5 Ligand-Receptor Complex Reveals a Wrench-like Architecture for IL-5Ralpha}, type = {Journal Article}, volume = 19, year = 2011 }

  %0 Journal Article %1 patino2011structure %A Patino, E. %A Kotzsch, A. %A Saremba, S. %A Nickel, J. %A Schmitz, W. %A Sebald, W. %A Mueller, T. D. %D 2011 %J Structure %N 12 %P 1864-75 %R 10.1016/j.str.2011.08.015 %T Structure Analysis of the IL-5 Ligand-Receptor Complex Reveals a Wrench-like Architecture for IL-5Ralpha %U http://www.ncbi.nlm.nih.gov/pubmed/22153509 %V 19
• Nickel, J., Kotzsch, A., Sebald, W., and Mueller, T.D. (2011) ‘Purification, crystallization and preliminary data analysis of the ligand-receptor complex of the growth and differentiation factor 5 variant R57A (GDF5R57A) and BMP receptor IA (BRIA)’, Acta Cryst F, 67(Pt 5), 551–5, available: https://doi.org/10.1107/S1744309111006907.
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  @article{nickel2011purification, author = {Nickel, J. and Kotzsch, A. and Sebald, W. and Mueller, T. D.}, journal = {Acta Cryst F}, keywords = {imported}, number = {Pt 5}, pages = {551-5}, title = {Purification, crystallization and preliminary data analysis of the ligand-receptor complex of the growth and differentiation factor 5 variant R57A (GDF5R57A) and BMP receptor IA (BRIA)}, type = {Journal Article}, volume = 67, year = 2011 }

  %0 Journal Article %1 nickel2011purification %A Nickel, J. %A Kotzsch, A. %A Sebald, W. %A Mueller, T. D. %D 2011 %J Acta Cryst F %N Pt 5 %P 551-5 %R 10.1107/S1744309111006907 %T Purification, crystallization and preliminary data analysis of the ligand-receptor complex of the growth and differentiation factor 5 variant R57A (GDF5R57A) and BMP receptor IA (BRIA) %U http://www.ncbi.nlm.nih.gov/pubmed/21543859 %V 67
• Dadacz-Narloch, B., Beyhl, D., Larisch, C., Lopez-Sanjurjo, E.J., Reski, R., Kuchitsu, K., Muller, T.D., Becker, D., Schonknecht, G., and Hedrich, R. (2011) ‘A novel calcium binding site in the slow vacuolar cation channel TPC1 senses luminal calcium levels’, Plant Cell, 23(7), 2696–707, available: https://doi.org/10.1105/tpc.111.086751.
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  @article{dadacznarloch2011novel, author = {Dadacz-Narloch, B. and Beyhl, D. and Larisch, C. and Lopez-Sanjurjo, E. J. and Reski, R. and Kuchitsu, K. and Muller, T. D. and Becker, D. and Schonknecht, G. and Hedrich, R.}, journal = {Plant Cell}, keywords = {imported}, number = 7, pages = {2696-707}, title = {A novel calcium binding site in the slow vacuolar cation channel TPC1 senses luminal calcium levels}, type = {Journal Article}, volume = 23, year = 2011 }

  %0 Journal Article %1 dadacznarloch2011novel %A Dadacz-Narloch, B. %A Beyhl, D. %A Larisch, C. %A Lopez-Sanjurjo, E. J. %A Reski, R. %A Kuchitsu, K. %A Muller, T. D. %A Becker, D. %A Schonknecht, G. %A Hedrich, R. %D 2011 %J Plant Cell %N 7 %P 2696-707 %R 10.1105/tpc.111.086751 %T A novel calcium binding site in the slow vacuolar cation channel TPC1 senses luminal calcium levels %U http://www.ncbi.nlm.nih.gov/pubmed/21764990 %V 23
• Seher, A., Nickel, J., Mueller, T.D., Kneitz, S., Gebhardt, S., ter Vehn, T.M., Schlunck, G., and Sebald, W. (2011) ‘Gene expression profiling of connective tissue growth factor (CTGF) stimulated primary human tenon fibroblasts reveals an inflammatory and wound healing response in vitro’, Molecular Vision, 17, 53–62, available: http://www.ncbi.nlm.nih.gov/pubmed/21245951.
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  @article{seher2011expression, author = {Seher, A. and Nickel, J. and Mueller, T. D. and Kneitz, S. and Gebhardt, S. and ter Vehn, T. M. and Schlunck, G. and Sebald, W.}, journal = {Molecular Vision}, keywords = {imported}, pages = {53-62}, title = {Gene expression profiling of connective tissue growth factor (CTGF) stimulated primary human tenon fibroblasts reveals an inflammatory and wound healing response in vitro}, type = {Journal Article}, volume = 17, year = 2011 }

  %0 Journal Article %1 seher2011expression %A Seher, A. %A Nickel, J. %A Mueller, T. D. %A Kneitz, S. %A Gebhardt, S. %A ter Vehn, T. M. %A Schlunck, G. %A Sebald, W. %D 2011 %J Molecular Vision %P 53-62 %T Gene expression profiling of connective tissue growth factor (CTGF) stimulated primary human tenon fibroblasts reveals an inflammatory and wound healing response in vitro %U http://www.ncbi.nlm.nih.gov/pubmed/21245951 %V 17
• Baljuls, A., Mahr, R., Schwarzenau, I., Muller, T., Polzien, L., Hekman, M., and Rapp, U.R. (2011) ‘Single substitution within the RKTR motif impairs kinase activity but promotes dimerization of RAF kinase’, J Biol Chem, 286(18), 16491–503, available: https://doi.org/10.1074/jbc.M110.194167.
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  @article{baljuls2011single, author = {Baljuls, A. and Mahr, R. and Schwarzenau, I. and Muller, T. and Polzien, L. and Hekman, M. and Rapp, U. R.}, journal = {J Biol Chem}, keywords = {imported}, number = 18, pages = {16491-503}, title = {Single substitution within the RKTR motif impairs kinase activity but promotes dimerization of RAF kinase}, type = {Journal Article}, volume = 286, year = 2011 }

  %0 Journal Article %1 baljuls2011single %A Baljuls, A. %A Mahr, R. %A Schwarzenau, I. %A Muller, T. %A Polzien, L. %A Hekman, M. %A Rapp, U. R. %D 2011 %J J Biol Chem %N 18 %P 16491-503 %R 10.1074/jbc.M110.194167 %T Single substitution within the RKTR motif impairs kinase activity but promotes dimerization of RAF kinase %U http://www.ncbi.nlm.nih.gov/pubmed/21454547 %V 286
• {Billington, C.J., Fiebig, J.E., Forsman, C.L., Pham, L., Burbach, N., Sun, M., Jaskoll, T., Mansky, K., Gopalakrishnan, R., O’Connor, M.B., Mueller, T.D., and Petryk, A. (2011) ‘Glycosylation of Twisted Gastrulation is Required for BMP Binding and Activity during Craniofacial Development’, Front Physiol, 2, 59, available: https://doi.org/10.3389/fphys.2011.00059.
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  @article{billingtoncj2011glycosylation, author = {{Billington, C. J.}, Jr. and Fiebig, J. E. and Forsman, C. L. and Pham, L. and Burbach, N. and Sun, M. and Jaskoll, T. and Mansky, K. and Gopalakrishnan, R. and O'Connor, M. B. and Mueller, T. D. and Petryk, A.}, journal = {Front Physiol}, keywords = {imported}, pages = 59, title = {Glycosylation of Twisted Gastrulation is Required for BMP Binding and Activity during Craniofacial Development}, type = {Journal Article}, volume = 2, year = 2011 }

  %0 Journal Article %1 billingtoncj2011glycosylation %A {Billington, C. J.} %A Fiebig, J. E. %A Forsman, C. L. %A Pham, L. %A Burbach, N. %A Sun, M. %A Jaskoll, T. %A Mansky, K. %A Gopalakrishnan, R. %A O'Connor, M. B. %A Mueller, T. D. %A Petryk, A. %D 2011 %J Front Physiol %P 59 %R 10.3389/fphys.2011.00059 %T Glycosylation of Twisted Gastrulation is Required for BMP Binding and Activity during Craniofacial Development %U http://www.ncbi.nlm.nih.gov/pubmed/21941513 %V 2

• Marcel, D., Muller, T., Hedrich, R., and Geiger, D. (2010) ‘K+ transport characteristics of the plasma membrane tandem-pore channel TPK4 and pore chimeras with its vacuolar homologs’, FEBS Lett, 584(11), 2433–9, available: https://doi.org/10.1016/j.febslet.2010.04.038.
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  @article{marcel2010transport, author = {Marcel, D. and Muller, T. and Hedrich, R. and Geiger, D.}, journal = {FEBS Lett}, keywords = {tdmueller}, number = 11, pages = {2433-9}, title = {K+ transport characteristics of the plasma membrane tandem-pore channel TPK4 and pore chimeras with its vacuolar homologs}, type = {Journal Article}, volume = 584, year = 2010 }

  %0 Journal Article %1 marcel2010transport %A Marcel, D. %A Muller, T. %A Hedrich, R. %A Geiger, D. %D 2010 %J FEBS Lett %N 11 %P 2433-9 %R 10.1016/j.febslet.2010.04.038 %T K+ transport characteristics of the plasma membrane tandem-pore channel TPK4 and pore chimeras with its vacuolar homologs %U http://www.ncbi.nlm.nih.gov/pubmed/20412800 %V 584
• Harth, S., Kotzsch, A., Sebald, W., and Mueller, T.D. (2010) ‘Crystallization of BMP receptor type IA bound to the antibody Fab fragment AbD1556’, Acta Crystallogr Sect F Struct Biol Cryst Commun, 66(Pt 8), 964–8, available: https://doi.org/10.1107/S1744309110024681.
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  @article{harth2010crystallization, author = {Harth, S. and Kotzsch, A. and Sebald, W. and Mueller, T. D.}, journal = {Acta Crystallogr Sect F Struct Biol Cryst Commun}, keywords = {imported}, number = {Pt 8}, pages = {964-8}, title = {Crystallization of BMP receptor type IA bound to the antibody Fab fragment AbD1556}, type = {Journal Article}, volume = 66, year = 2010 }

  %0 Journal Article %1 harth2010crystallization %A Harth, S. %A Kotzsch, A. %A Sebald, W. %A Mueller, T. D. %D 2010 %J Acta Crystallogr Sect F Struct Biol Cryst Commun %N Pt 8 %P 964-8 %R 10.1107/S1744309110024681 %T Crystallization of BMP receptor type IA bound to the antibody Fab fragment AbD1556 %U http://www.ncbi.nlm.nih.gov/pubmed/20693682 %V 66
• Sebald, W., Nickel, J., Zhang, J.L., and Mueller, T.D. (2010) ‘Molecular basis of cytokine signalling--theme and variations’, FEBS J, 277(1), 106–18, available: https://doi.org/10.1111/j.1742-4658.2009.07480.x.
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  @article{sebald2010molecular, author = {Sebald, W. and Nickel, J. and Zhang, J. L. and Mueller, T. D.}, journal = {FEBS J}, keywords = {imported}, number = 1, pages = {106-18}, title = {Molecular basis of cytokine signalling–theme and variations}, type = {Journal Article}, volume = 277, year = 2010 }

  %0 Journal Article %1 sebald2010molecular %A Sebald, W. %A Nickel, J. %A Zhang, J. L. %A Mueller, T. D. %D 2010 %J FEBS J %N 1 %P 106-18 %R 10.1111/j.1742-4658.2009.07480.x %T Molecular basis of cytokine signalling--theme and variations %U http://www.ncbi.nlm.nih.gov/pubmed/19951357 %V 277
• Piters, E., Culha, C., Moester, M., Van Bezooijen, R., Adriaensen, D., Mueller, T., Weidauer, S., Jennes, K., de Freitas, F., Lowik, C., Timmermans, J.P., Van Hul, W., and Papapoulos, S. (2010) ‘First missense mutation in the SOST gene causing sclerosteosis by loss of sclerostin function’, Hum Mutat, 31(7), E1526–43, available: https://doi.org/10.1002/humu.21274.
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  @article{piters2010first, author = {Piters, E. and Culha, C. and Moester, M. and Van Bezooijen, R. and Adriaensen, D. and Mueller, T. and Weidauer, S. and Jennes, K. and de Freitas, F. and Lowik, C. and Timmermans, J. P. and Van Hul, W. and Papapoulos, S.}, journal = {Hum Mutat}, keywords = {imported}, number = 7, pages = {E1526-43}, title = {First missense mutation in the SOST gene causing sclerosteosis by loss of sclerostin function}, type = {Journal Article}, volume = 31, year = 2010 }

  %0 Journal Article %1 piters2010first %A Piters, E. %A Culha, C. %A Moester, M. %A Van Bezooijen, R. %A Adriaensen, D. %A Mueller, T. %A Weidauer, S. %A Jennes, K. %A de Freitas, F. %A Lowik, C. %A Timmermans, J. P. %A Van Hul, W. %A Papapoulos, S. %D 2010 %J Hum Mutat %N 7 %P E1526-43 %R 10.1002/humu.21274 %T First missense mutation in the SOST gene causing sclerosteosis by loss of sclerostin function %U http://www.ncbi.nlm.nih.gov/pubmed/20583295 %V 31
• Krause, C., Korchynskyi, O., de Rooij, K., Weidauer, S.E., de Gorter, D.J., van Bezooijen, R.L., Hatsell, S., Economides, A.N., Mueller, T.D., Lowik, C.W., and ten Dijke, P. (2010) ‘Distinct modes of inhibition by sclerostin on bone morphogenetic protein and Wnt signaling pathways’, J Biol Chem, 285(53), 41614–26, available: https://doi.org/10.1074/jbc.M110.153890.
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  @article{krause2010distinct, author = {Krause, C. and Korchynskyi, O. and de Rooij, K. and Weidauer, S. E. and de Gorter, D. J. and van Bezooijen, R. L. and Hatsell, S. and Economides, A. N. and Mueller, T. D. and Lowik, C. W. and ten Dijke, P.}, journal = {J Biol Chem}, keywords = {imported}, number = 53, pages = {41614-26}, title = {Distinct modes of inhibition by sclerostin on bone morphogenetic protein and Wnt signaling pathways}, type = {Journal Article}, volume = 285, year = 2010 }

  %0 Journal Article %1 krause2010distinct %A Krause, C. %A Korchynskyi, O. %A de Rooij, K. %A Weidauer, S. E. %A de Gorter, D. J. %A van Bezooijen, R. L. %A Hatsell, S. %A Economides, A. N. %A Mueller, T. D. %A Lowik, C. W. %A ten Dijke, P. %D 2010 %J J Biol Chem %N 53 %P 41614-26 %R 10.1074/jbc.M110.153890 %T Distinct modes of inhibition by sclerostin on bone morphogenetic protein and Wnt signaling pathways %U http://www.ncbi.nlm.nih.gov/pubmed/20952383 %V 285
• Harth, S., Kotzsch, A., Hu, J., Sebald, W., and Mueller, T.D. (2010) ‘A selection fit mechanism in BMP receptor IA as a possible source for BMP ligand-receptor promiscuity’, PLoS One, 5(9), available: https://doi.org/10.1371/journal.pone.0013049.
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  @article{harth2010selection, author = {Harth, S. and Kotzsch, A. and Hu, J. and Sebald, W. and Mueller, T. D.}, journal = {PLoS One}, keywords = {imported}, number = 9, title = {A selection fit mechanism in BMP receptor IA as a possible source for BMP ligand-receptor promiscuity}, type = {Journal Article}, volume = 5, year = 2010 }

  %0 Journal Article %1 harth2010selection %A Harth, S. %A Kotzsch, A. %A Hu, J. %A Sebald, W. %A Mueller, T. D. %D 2010 %J PLoS One %N 9 %R 10.1371/journal.pone.0013049 %T A selection fit mechanism in BMP receptor IA as a possible source for BMP ligand-receptor promiscuity %U http://www.ncbi.nlm.nih.gov/pubmed/20927405 %V 5

• Spindler, V., Heupel, W.-M., Efthymiadis, A., Schmidt, E., Eming, R., Rankl, C., Hinterdorfer, P., Müller, T., Drenckhahn, D., and Waschke, J. (2009) ‘Desmocollin 3-mediated Binding Is Crucial for Keratinocyte Cohesion and Is Impaired in Pemphigus’, Journal of Biological Chemistry, 284(44), 30556–30564, available: https://doi.org/10.1074/jbc.m109.024810.
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  @article{Spindler_2009, author = {Spindler, Volker and Heupel, Wolfgang-Moritz and Efthymiadis, Athina and Schmidt, Enno and Eming, Rüdiger and Rankl, Christian and Hinterdorfer, Peter and Müller, Thomas and Drenckhahn, Detlev and Waschke, Jens}, journal = {Journal of Biological Chemistry}, keywords = {myown}, month = 10, number = 44, pages = {30556–30564}, publisher = {Elsevier {BV}}, title = {Desmocollin 3-mediated Binding Is Crucial for Keratinocyte Cohesion and Is Impaired in Pemphigus}, volume = 284, year = 2009 }

  %0 Journal Article %1 Spindler_2009 %A Spindler, Volker %A Heupel, Wolfgang-Moritz %A Efthymiadis, Athina %A Schmidt, Enno %A Eming, Rüdiger %A Rankl, Christian %A Hinterdorfer, Peter %A Müller, Thomas %A Drenckhahn, Detlev %A Waschke, Jens %D 2009 %I Elsevier {BV} %J Journal of Biological Chemistry %N 44 %P 30556--30564 %R 10.1074/jbc.m109.024810 %T Desmocollin 3-mediated Binding Is Crucial for Keratinocyte Cohesion and Is Impaired in Pemphigus %U https://doi.org/10.1074%2Fjbc.m109.024810 %V 284
• Schmitt, B.M., Gorbunov, D., Schlachtbauer, P., Egenberger, B., Gorboulev, V., Wischmeyer, E., Muller, T., and Koepsell, H. (2009) ‘Charge-to-substrate ratio during organic cation uptake by rat OCT2 is voltage dependent and altered by exchange of glutamate 448 with glutamine’, Am J Physiol Renal Physiol, 296(4), F709–22, available: https://doi.org/10.1152/ajprenal.90323.2008.
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  @article{schmitt2009chargetosubstrate, author = {Schmitt, B. M. and Gorbunov, D. and Schlachtbauer, P. and Egenberger, B. and Gorboulev, V. and Wischmeyer, E. and Muller, T. and Koepsell, H.}, journal = {Am J Physiol Renal Physiol}, keywords = {imported}, number = 4, pages = {F709-22}, title = {Charge-to-substrate ratio during organic cation uptake by rat OCT2 is voltage dependent and altered by exchange of glutamate 448 with glutamine}, type = {Journal Article}, volume = 296, year = 2009 }

  %0 Journal Article %1 schmitt2009chargetosubstrate %A Schmitt, B. M. %A Gorbunov, D. %A Schlachtbauer, P. %A Egenberger, B. %A Gorboulev, V. %A Wischmeyer, E. %A Muller, T. %A Koepsell, H. %D 2009 %J Am J Physiol Renal Physiol %N 4 %P F709-22 %R 10.1152/ajprenal.90323.2008 %T Charge-to-substrate ratio during organic cation uptake by rat OCT2 is voltage dependent and altered by exchange of glutamate 448 with glutamine %U http://www.ncbi.nlm.nih.gov/pubmed/19211691 %V 296
• Heupel, W.M., Muller, T., Efthymiadis, A., Schmidt, E., Drenckhahn, D., and Waschke, J. (2009) ‘Peptides Targeting the Desmoglein 3 Adhesive Interface Prevent Autoantibody-induced Acantholysis in Pemphigus’, J Biol Chem, 284(13), 8589–95, available: https://doi.org/10.1074/jbc.M808813200.
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  @article{heupel2009peptides, author = {Heupel, W. M. and Muller, T. and Efthymiadis, A. and Schmidt, E. and Drenckhahn, D. and Waschke, J.}, journal = {J Biol Chem}, keywords = {imported}, number = 13, pages = {8589-95}, title = {Peptides Targeting the Desmoglein 3 Adhesive Interface Prevent Autoantibody-induced Acantholysis in Pemphigus}, type = {Journal Article}, volume = 284, year = 2009 }

  %0 Journal Article %1 heupel2009peptides %A Heupel, W. M. %A Muller, T. %A Efthymiadis, A. %A Schmidt, E. %A Drenckhahn, D. %A Waschke, J. %D 2009 %J J Biol Chem %N 13 %P 8589-95 %R 10.1074/jbc.M808813200 %T Peptides Targeting the Desmoglein 3 Adhesive Interface Prevent Autoantibody-induced Acantholysis in Pemphigus %U http://www.ncbi.nlm.nih.gov/pubmed/19164289 %V 284
• Weidauer, S.E., Schmieder, P., Beerbaum, M., Schmitz, W., Oschkinat, H., and Mueller, T.D. (2009) ‘NMR structure of the Wnt modulator protein Sclerostin’, Biochem Biophys Res Commun, 380(1), 160–5, available: https://doi.org/10.1016/j.bbrc.2009.01.062.
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  @article{weidauer2009structure, author = {Weidauer, S. E. and Schmieder, P. and Beerbaum, M. and Schmitz, W. and Oschkinat, H. and Mueller, T. D.}, journal = {Biochem Biophys Res Commun}, keywords = {imported}, number = 1, pages = {160-5}, title = {NMR structure of the Wnt modulator protein Sclerostin}, type = {Journal Article}, volume = 380, year = 2009 }

  %0 Journal Article %1 weidauer2009structure %A Weidauer, S. E. %A Schmieder, P. %A Beerbaum, M. %A Schmitz, W. %A Oschkinat, H. %A Mueller, T. D. %D 2009 %J Biochem Biophys Res Commun %N 1 %P 160-5 %R 10.1016/j.bbrc.2009.01.062 %T NMR structure of the Wnt modulator protein Sclerostin %U http://www.ncbi.nlm.nih.gov/pubmed/19166819 %V 380
• Filatova, A., Leyerer, M., Gorboulev, V., Chintalapati, C., Reinders, Y., Muller, T.D., Srinivasan, A., Hubner, S., and Koepsell, H. (2009) ‘Novel shuttling domain in a regulator (RSC1A1) of transporter SGLT1 steers cell cycle-dependent nuclear location’, Traffic, 10(11), 1599–618, available: https://doi.org/10.1111/j.1600-0854.2009.00982.x.
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  @article{filatova2009novel, author = {Filatova, A. and Leyerer, M. and Gorboulev, V. and Chintalapati, C. and Reinders, Y. and Muller, T. D. and Srinivasan, A. and Hubner, S. and Koepsell, H.}, journal = {Traffic}, keywords = {imported}, number = 11, pages = {1599-618}, title = {Novel shuttling domain in a regulator (RSC1A1) of transporter SGLT1 steers cell cycle-dependent nuclear location}, type = {Journal Article}, volume = 10, year = 2009 }

  %0 Journal Article %1 filatova2009novel %A Filatova, A. %A Leyerer, M. %A Gorboulev, V. %A Chintalapati, C. %A Reinders, Y. %A Muller, T. D. %A Srinivasan, A. %A Hubner, S. %A Koepsell, H. %D 2009 %J Traffic %N 11 %P 1599-618 %R 10.1111/j.1600-0854.2009.00982.x %T Novel shuttling domain in a regulator (RSC1A1) of transporter SGLT1 steers cell cycle-dependent nuclear location %U http://www.ncbi.nlm.nih.gov/pubmed/19765263 %V 10