Structure of an endosomal signaling GPCR-G protein-β-arrestin megacomplex.
Classically, G-protein-coupled receptors (GPCRs) are thought to activate G protein from the plasma membrane and are subsequently desensitized by β-arrestin (β-arr). However, some GPCRs continue to signal through G protein from internalized compartments, mediated by a GPCR-G protein-β-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 β-arr to the core and phosphorylated tail, respectively, of a single active human chimeric β2-adrenergic receptor with the C-terminal tail of the arginine vasopressin type 2 receptor (β2V2R). All three components adopt their canonical active conformations, suggesting that a single megaplex GPCR is capable of simultaneously activating G protein and β-arr. Our findings provide a structural basis for GPCR-mediated sustained internalized G protein signaling.
Nguyen, AH; Thomsen, ARB; Cahill, TJ; Huang, R; Huang, L-Y; Marcink, T; Clarke, OB; Heissel, S; Masoudi, A; Ben-Hail, D; Samaan, F; Dandey, VP; Tan, YZ; Hong, C; Mahoney, JP; Triest, S; Little, J; Chen, X; Sunahara, R; Steyaert, J; Molina, H; Yu, Z; des Georges, A; Lefkowitz, RJ
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