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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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