Journal Article

Structure of an endosomal signaling GPCR–G protein–β-arrestin megacomplex

Li-Yin, Huang, Clarke, Oliver B, Masoudi, Ali, Mahoney, Jacob P, Cahill, Thomas J, Lefkowitz, Robert J, Nguyen, Anthony H, Yong Zi Tan, Steyaert, Jan, Dandey, Venkata P, Amedee des Georges, Ben-Hail, Danya, Samaan, Fadi, Triest, Sarah, Sunahara, Roger, Hong, Chuan, Chen, Xin, Huang, Rick, Marcink, Tara, Molina, Henrik, Thomsen, Alex R B, Heissel, Søren, Little, John, Yu, Zhiheng

2019

Overview

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.

• Publisher: Nature Publishing Group
• Subject: Adrenergic receptors / Argipressin / Arrestin / Electron microscopy / G protein-coupled receptors / Membrane proteins / Proteins / Receptors / Signaling / Vasopressin