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bioRxiv · 10.1101/2021.12.16.472984

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

Klenk, C.·Hommers, L.·Lohse, M. J.
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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 Gs and increased activation of Gq compared to wild-type PTH1R. These findings indicate that the extracellular domain modulates PTH1R signaling specificity, and that its cleavage affects receptor signaling.

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Klenk, C., Hommers, L., Lohse, M. J.. 2021-12-17. Proteolytic cleavage of the extracellular domain affects signaling of parathyroid hormone receptor 1. https://doi.org/10.1101/2021.12.16.472984

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