Functional competence of a partially engaged GPCR-?-arrestin complex.

ABSTRACT: G Protein-coupled receptors (GPCRs) constitute the largest family of cell surface receptors and drug targets. GPCR signalling and desensitization is critically regulated by ?-arrestins (?arr). GPCR-?arr interaction is biphasic where the phosphorylated carboxyl terminus of GPCRs docks to the N-domain of ?arr first and then seven transmembrane core of the receptor engages with ?arr. It is currently unknown whether fully engaged GPCR-?arr complex is essential for functional outcomes or partially engaged complex can also be functionally competent. Here we assemble partially and fully engaged complexes of a chimeric ?2V2R with ?arr1, and discover that the core interaction is dispensable for receptor endocytosis, ERK MAP kinase binding and activation. Furthermore, we observe that carvedilol, a ?arr biased ligand, does not promote detectable engagement between ?arr1 and the receptor core. These findings uncover a previously unknown aspect of GPCR-?arr interaction and provide novel insights into GPCR signalling and regulatory paradigms.

SUBMITTER: Kumari P 

PROVIDER: S-EPMC5105198 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature