Biased signalling is structurally encoded as an autoproteolysis event in adhesion G protein-coupled receptor Latrophilin-3/ADGRL3.

Autor: Ojeda-Muñiz EY; Department of Cell Biology, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (Cinvestav), México City, Mexico., Rodríguez-Hernández B; Department of Cell Biology, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (Cinvestav), México City, Mexico., Correoso-Braña KG; Department of Cell Biology, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (Cinvestav), México City, Mexico., Segura-Landa PL; Department of Cell Biology, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (Cinvestav), México City, Mexico., Boucard AA; Department of Cell Biology, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (Cinvestav), México City, Mexico.
Jazyk: angličtina
Zdroj: Basic & clinical pharmacology & toxicology [Basic Clin Pharmacol Toxicol] 2023 Oct; Vol. 133 (4), pp. 342-352. Date of Electronic Publication: 2023 Aug 01.
DOI: 10.1111/bcpt.13927
Abstrakt: Adhesion G protein-coupled receptors (aGPCRs) possess a unique topology, including the presence of a GPCR proteolysis site (GPS), which, upon autoproteolysis, generates two functionally distinct fragments that remain non-covalently associated at the plasma membrane. A proposed activation mechanism for aGPCRs involves the exposure of a tethered agonist, which depends on cleavage at the GPS. However, this hypothesis has been challenged by the observation that non-cleavable aGPCRs exhibit constitutive activity, thus making the function of GPS cleavage widely enigmatic. In this study, we sought to elucidate the function of GPS-mediated cleavage through the study of G protein coupling with Latrophilin-3/ADGRL3, a prototypical aGPCR involved in synapse formation and function. Using BRET-based G protein biosensors, we reveal that an autoproteolysis-deficient mutant of ADGRL3 retains constitutive activity. Surprisingly, we uncover that cleavage deficiency leads to a signalling bias directed at potentiating the activity of select G proteins such as Gi2 and G12/13. These data unveil the underpinnings of biased signalling for aGPCRs defined by GPS autoproteolysis.
(© 2023 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)
Databáze: MEDLINE
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