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

ISSN:

1664-2392

Publisher:

Frontiers Media SA

Volume:

Page Range:

839351

Date: