Proteolytic cleavage of the extracellular domain affects signaling of parathyroid hormone 1 receptor

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Item Type:	Article
Title:	Proteolytic cleavage of the extracellular domain affects signaling of parathyroid hormone 1 receptor
Creators Name:	Klenk, C., Hommers, L. and Lohse, M.J.
Abstract:	Parathyroid hormone 1 receptor (PTH1R) is a member of the class B family of G protein-coupled receptors, which are characterized by a large extracellular domain required for ligand binding. We have previously shown that the extracellular domain of PTH1R is subject to metalloproteinase cleavage in vivo that is regulated by ligand-induced receptor trafficking and leads to impaired stability of PTH1R. In this work, we localize the cleavage site in the first loop of the extracellular domain using amino-terminal protein sequencing of purified receptor and by mutagenesis studies. We further show, that a receptor mutant not susceptible to proteolytic cleavage exhibits reduced signaling to G(s) and increased activation of G(q) compared to wild-type PTH1R. These findings indicate that the extracellular domain modulates PTH1R signaling specificity, and that its cleavage affects receptor signaling.
Keywords:	GPCRs, Parathyroid Hormone 1 Receptor, Matrix Metalloproteinase, Ectodomain Cleavage, Biased Signaling
Source:	Frontiers in Endocrinology
ISSN:	1664-2392
Publisher:	Frontiers Media SA
Volume:	13
Page Range:	839351
Date:	22 February 2022
Official Publication:	https://doi.org/10.3389/fendo.2022.839351
PubMed:	View item in PubMed

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