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.
- 1,
- 1/*agonists/*chemistry
- agonists/chemistry;
- animals
- animals;
- binding
- binding;
- cell
- cells;
- chemistry
- chemistry;
- cho
- complementary,
- complementary/metabolism
- cricetinae
- cricetinae;
- cricetulus
- cricetulus;
- disulfides
- disulfides;
- dna,
- epitopes,
- epitopes/chemistry
- exons
- exons;
- expression
- g-protein-coupled,
- g-protein-coupled/chemistry
- gene
- hormone,
- humans
- humans;
- ligands
- ligands;
- line,
- metabolism;
- parathyroid
- post-translational
- post-translational;
- processing,
- protein
- rats
- rats;
- receptor
- receptor,
- receptors,
- regulation
- regulation;
- structure,
- tertiary
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