Distinct phosphorylation sites in a prototypical GPCR differently orchestrate ?-arrestin interaction, trafficking, and signaling.

ABSTRACT: Agonist-induced phosphorylation of G protein-coupled receptors (GPCRs) is a key determinant for their interaction with ?-arrestins (?arrs) and subsequent functional responses. Therefore, it is important to decipher the contribution and interplay of different receptor phosphorylation sites in governing ?arr interaction and functional outcomes. Here, we find that several phosphorylation sites in the human vasopressin receptor (V2R), positioned either individually or in clusters, differentially contribute to ?arr recruitment, trafficking, and ERK1/2 activation. Even a single phosphorylation site in V2R, suitably positioned to cross-talk with a key residue in ?arrs, has a decisive contribution in ?arr recruitment, and its mutation results in strong G-protein bias. Molecular dynamics simulation provides mechanistic insights into the pivotal role of this key phosphorylation site in governing the stability of ?arr interaction and regulating the interdomain rotation in ?arrs. Our findings uncover important structural aspects to better understand the framework of GPCR-?arr interaction and biased signaling.

SUBMITTER: Dwivedi-Agnihotri H 

PROVIDER: S-EPMC7486103 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature