1. Structure of an endosomal signaling GPCR-G protein-β-arrestin megacomplex
- Author
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Jan Steyaert, Søren Heissel, Thomas J. Cahill, Tara C. Marcink, Li-Yin Huang, Oliver B. Clarke, Robert J. Lefkowitz, Sarah Triest, Chuan Hong, Rick Huang, Anthony H. Nguyen, Henrik Molina, Yong Zi Tan, Fadi Samaan, John Little, Alex R.B. Thomsen, Amedee des Georges, Xin Chen, Danya Ben-Hail, Ali Masoudi, Venkata P. Dandey, Roger K. Sunahara, Jacob P. Mahoney, Zhiheng Yu, Department of Bio-engineering Sciences, and Structural Biology Brussels
- Subjects
Models, Molecular ,Receptors, Vasopressin ,G protein ,Endosome ,Protein Conformation ,Biophysics ,beta-2 ,Endosomes ,Medical and Health Sciences ,Article ,Receptors, G-Protein-Coupled ,03 medical and health sciences ,G-Protein-Coupled ,0302 clinical medicine ,Protein structure ,Structural Biology ,GTP-Binding Proteins ,Models ,Receptors ,Arrestin ,Animals ,Humans ,Receptor ,Molecular Biology ,beta-Arrestins ,030304 developmental biology ,G protein-coupled receptor ,0303 health sciences ,Chemistry ,Cryoelectron Microscopy ,Molecular ,Biological Sciences ,Cell biology ,Adrenergic ,Chemical Sciences ,Phosphorylation ,Cattle ,Receptors, Adrenergic, beta-2 ,Generic health relevance ,Signal transduction ,030217 neurology & neurosurgery ,Vasopressin ,Signal Transduction ,Developmental Biology - Abstract
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.
- Published
- 2019