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

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

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.

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