Structure of an endosomal signaling GPCR-G protein-?-arrestin megacomplex.

ABSTRACT: Classically, G-protein-coupled receptors (GPCRs) are thought to activate G protein from the plasma membrane and are subsequently desensitized by ?-arrestin (?-arr). However, some GPCRs continue to signal through G protein from internalized compartments, mediated by a GPCR-G protein-?-arr 'megaplex'. Nevertheless, the molecular architecture of the megaplex remains unknown. Here, we present its cryo-electron microscopy structure, which shows simultaneous engagement of human G protein and bovine ?-arr to the core and phosphorylated tail, respectively, of a single active human chimeric ?2-adrenergic receptor with the C-terminal tail of the arginine vasopressin type 2 receptor (?2V2R). All three components adopt their canonical active conformations, suggesting that a single megaplex GPCR is capable of simultaneously activating G protein and ?-arr. Our findings provide a structural basis for GPCR-mediated sustained internalized G protein signaling.

SUBMITTER: Nguyen AH 

PROVIDER: S-EPMC7108872 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature