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Structure of an endosomal signaling GPCR-G protein-beta-arrestin megacomplex

Journal Contribution - Journal Article

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 β 2-adrenergic receptor with the C-terminal tail of the arginine vasopressin type 2 receptor (β 2V 2R). 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.

Journal: Nature Structural & Molecular Biology
ISSN: 1545-9993
Issue: 12
Volume: 26
Pages: 1123-1131
Publication year:2019
CSS-citation score:3
Accessibility:Closed