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ADAM19 cleaves the PTH receptor and associates with brachydactyly type E

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Item Type:Article
Title:ADAM19 cleaves the PTH receptor and associates with brachydactyly type E
Creators Name:Aydin, A. and Klenk, C. and Nemec, K. and Işbilir, Ali and Martin, L.M. and Zauber, H. and Rrustemi, T. and Toka, H.R. and Schuster, H. and Gong, M. and Stricker, S. and Bock, A. and Bähring, S. and Selbach, M. and Lohse, M.J. and Luft, F.C.
Abstract:Brachydactyly type E (BDE), shortened metacarpals, metatarsals, cone-shaped epiphyses, and short stature commonly occurs as a sole phenotype. Parathyroid hormone-like protein (PTHrP) has been shown to be responsible in all forms to date, either directly or indirectly. We used linkage and then whole genome sequencing in a small pedigree, to elucidate BDE and identified a truncated disintegrin-and-metalloproteinase-19 (ADAM19) allele in all affected family members, but not in nonaffected persons. Since we had shown earlier that the extracellular domain of the parathyroid hormone receptor (PTHR1) is subject to an unidentified metalloproteinase cleavage, we tested the hypothesis that ADAM19 is a sheddase for PTHR1. WT ADAM19 cleaved PTHR1, while mutated ADAM-19 did not. We mapped the cleavage site that we verified with mass spectrometry between amino acids 64-65. ADAM-19 cleavage increased G(q) and decreased G(s) activation. Moreover, perturbed PTHR1 cleavage by ADAM19 increased ß-arrestin2 recruitment, while cAMP accumulation was not altered. We suggest that ADAM19 serves as a regulatory element for PTHR1 and could be responsible for BDE. This sheddase may affect other PTHrP or PTH-related functions.
Keywords:ADAM Proteins, Brachydactyly, Metalloproteases, Parathyroid Hormone-Related Protein, Type 1 Parathyroid Hormone Receptor
Source:Life Science Alliance
Publisher:Life Science Alliance
Page Range:e202302400
Date:April 2024
Official Publication:https://doi.org/10.26508/lsa.202302400
PubMed:View item in PubMed

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