Catalytic activation of ?-arrestin by GPCRs.

ABSTRACT: ?-arrestins are critical regulator and transducer proteins for G-protein-coupled receptors (GPCRs). ?-arrestin is widely believed to be activated by forming a stable and stoichiometric GPCR-?-arrestin scaffold complex, which requires and is driven by the phosphorylated tail of the GPCR. Here we demonstrate a distinct and additional mechanism of ?-arrestin activation that does not require stable GPCR-?-arrestin scaffolding or the GPCR tail. Instead, it occurs through transient engagement of the GPCR core, which destabilizes a conserved inter-domain charge network in ?-arrestin. This promotes capture of ?-arrestin at the plasma membrane and its accumulation in clathrin-coated endocytic structures (CCSs) after dissociation from the GPCR, requiring a series of interactions with membrane phosphoinositides and CCS-lattice proteins. ?-arrestin clustering in CCSs in the absence of the upstream activating GPCR is associated with a ?-arrestin-dependent component of the cellular ERK (extracellular signal-regulated kinase) response. These results delineate a discrete mechanism of cellular ?-arrestin function that is activated catalytically by GPCRs.

SUBMITTER: Eichel K 

PROVIDER: S-EPMC6058965 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature