%0 Journal Article %1 Klenk2010 %A Klenk, C. %A Schulz, S. %A Calebiro, D. %A Lohse, M. J. %D 2010 %J J Biol Chem %K 1/*agonists/*chemistry Animals Binding CHO Cell Complementary/metabolism Cricetinae Cricetulus DNA, Disulfides Epitopes/chemistry Exons Expression G-Protein-Coupled/chemistry Gene Hormone, Humans Ligands Line, Parathyroid Post-Translational Processing, Protein Rats Regulation Structure, Tertiary Tumor Type Receptor %N 12 %P 8665-74 %T Agonist-regulated cleavage of the extracellular domain of parathyroid hormone receptor type 1 %U http://www.ncbi.nlm.nih.gov/pubmed/20080964 %V 285 %X The receptor for parathyroid hormone (PTHR) is a main regulator of calcium homeostasis and bone maintenance. As a member of class B of G protein-coupled receptors, it harbors a large extracellular domain, which is required for ligand binding. Here, we demonstrate that the PTHR extracellular domain is cleaved by a protease belonging to the family of extracellular metalloproteinases. We show that the cleavage takes place in a region of the extracellular domain that belongs to an unstructured loop connecting the ligand-binding parts and that the N-terminal 10-kDa fragment is connected to the receptor core by a disulfide bond. Cleaved receptor revealed reduced protein stability compared with noncleaved receptor, suggesting degradation of the whole receptor. In the presence of the agonistic peptides PTH(1-34), PTH(1-14), or PTH(1-31), the processing of the PTHR extracellular domain was inhibited, and receptor protein levels were stabilized. A processed form of the PTHR was also detected in human kidney. These findings suggest a new model of PTHR processing and regulation of its stability.

@article{Klenk2010, abstract = {The receptor for parathyroid hormone (PTHR) is a main regulator of calcium homeostasis and bone maintenance. As a member of class B of G protein-coupled receptors, it harbors a large extracellular domain, which is required for ligand binding. Here, we demonstrate that the PTHR extracellular domain is cleaved by a protease belonging to the family of extracellular metalloproteinases. We show that the cleavage takes place in a region of the extracellular domain that belongs to an unstructured loop connecting the ligand-binding parts and that the N-terminal 10-kDa fragment is connected to the receptor core by a disulfide bond. Cleaved receptor revealed reduced protein stability compared with noncleaved receptor, suggesting degradation of the whole receptor. In the presence of the agonistic peptides PTH(1-34), PTH(1-14), or PTH(1-31), the processing of the PTHR extracellular domain was inhibited, and receptor protein levels were stabilized. A processed form of the PTHR was also detected in human kidney. These findings suggest a new model of PTHR processing and regulation of its stability.}, added-at = {2010-12-14T18:12:02.000+0100}, author = {Klenk, C. and Schulz, S. and Calebiro, D. and Lohse, M. J.}, biburl = {https://www.bibsonomy.org/bibtex/2da7837f78773702598f490ce3302b1a2/pharmawuerz}, comment = {2838289}, endnotereftype = {Journal Article}, groups = {private}, interhash = {b78e8092b46d79e960cc95ef2cb2d175}, intrahash = {da7837f78773702598f490ce3302b1a2}, issn = {1083-351X (Electronic) 0021-9258 (Linking)}, journal = {J Biol Chem}, keywords = {1/*agonists/*chemistry Animals Binding CHO Cell Complementary/metabolism Cricetinae Cricetulus DNA, Disulfides Epitopes/chemistry Exons Expression G-Protein-Coupled/chemistry Gene Hormone, Humans Ligands Line, Parathyroid Post-Translational Processing, Protein Rats Regulation Structure, Tertiary Tumor Type Receptor}, month = {Mar 19}, note = {Klenk, Christoph Schulz, Stefan Calebiro, Davide Lohse, Martin J Research Support, Non-U.S. Gov't United States The Journal of biological chemistry J Biol Chem. 2010 Mar 19;285(12):8665-74. Epub 2010 Jan 15.}, number = 12, pages = {8665-74}, shorttitle = {Agonist-regulated cleavage of the extracellular domain of parathyroid hormone receptor type 1}, timestamp = {2010-12-14T18:20:39.000+0100}, title = {Agonist-regulated cleavage of the extracellular domain of parathyroid hormone receptor type 1}, url = {http://www.ncbi.nlm.nih.gov/pubmed/20080964}, volume = 285, year = 2010 }