Functional competence of a partially engaged GPCR-β-arrestin complex

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