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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. and 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
Publisher:Frontiers Media SA
Page Range:839351
Date:22 February 2022
Official Publication:https://doi.org/10.3389/fendo.2022.839351
PubMed:View item in PubMed
Related to:
http://edoc.mdc-berlin.de/21226/Preprint version

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