Agonist-regulated cleavage of the extracellular domain of parathyroid hormone receptor type 1.
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.
Klenk
Christoph
C
Institute of Pharmacology and Toxicology, Deutsche Forschungsgemeinschaft Research Center for Experimental Biomedicine, University of Wrzburg, 97078 Würzburg, Germany. klenk@toxi.uni-wuerzburg.de
Schulz
Stefan
S
Calebiro
Davide
D
Lohse
Martin J
MJ
D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D018076:DNA, Complementary / Q000378:metabolism; D004220:Disulfides; D000939:Epitopes / Q000737:chemistry; D005091:Exons; D005786:Gene Expression Regulation; D006801:Humans; D008024:Ligands; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D051381:Rats; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000819:agonists* / Q000737:chemistry*; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry
D018076:DNA, Complementary; D004220:Disulfides; D000939:Epitopes; D008024:Ligands; D044168:Receptor, Parathyroid Hormone, Type 1; D043562:Receptors, G-Protein-Coupled