ADAM19 cleaves the PTH receptor and associates with brachydactyly type E.

Henrik Zauber, Martin J Lohse, Herbert Schuster, Matthias Selbach, Christoph Klenk, Andreas Bock, Friedrich C Luft, Hakan R Toka, Atakan Aydin, Katarina Nemec, Ali Işbilir, Lisa M Martin, Trendelina Rrustemi, Maolian Gong, Sigmar Stricker, Sylvia Bähring

Journal: Life science alliance 2024;7(4):

PMID: 38331475

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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 and decreased G 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.

Address: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.; Experimental and Clinical Research Center, A Cooperation Between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité Universitätsmedizin, Berlin, Germany.; Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany.; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.; Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany.; Department of Structural Biology and Center of Excellence for Data-Driven Discovery, St. Jude Children's Research Hospital, Memphis, TN, USA.; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.; Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany.; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.; Experimental and Clinical Research Center, A Cooperation Between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité Universitätsmedizin, Berlin, Germany.; Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany.; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.; Rudolf-Boehm-Institute of Pharmacology and Toxicology, Medical Faculty, University of Leipzig, Leipzig, Germany.; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.; ISAR Bioscience Institute, Munich, Germany.; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany [email protected].; Experimental and Clinical Research Center, A Cooperation Between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité Universitätsmedizin, Berlin, Germany.

DOI: 10.26508/lsa.202302400

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https://antibodies.cancer.gov/detail/CPTC-PTHrP-1

MeSH Terms: Humans, Parathyroid Hormone-Related Protein, Brachydactyly, Receptor, Parathyroid Hormone, Type 1, Metalloproteases, ADAM Proteins