Agonist-regulated cleavage of the extracellular domain of parathyroid
hormone receptor type 1
C. Klenk, S. Schulz, D. Calebiro, and M. Lohse. J Biol Chem, 285 (12):
8665-74(March 2010)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..
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.
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.
%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
}