1. Structure of an endosomal signaling GPCR-G protein-β-arrestin megacomplex.
- Author
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Nguyen AH, Thomsen ARB, Cahill TJ 3rd, Huang R, Huang LY, 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 4th, Chen X, Sunahara R, Steyaert J, Molina H, Yu Z, des Georges A, and Lefkowitz RJ
- Subjects
- Animals, Cattle, Cryoelectron Microscopy, Endosomes metabolism, GTP-Binding Proteins chemistry, GTP-Binding Proteins ultrastructure, Humans, Models, Molecular, Protein Conformation, Receptors, Adrenergic, beta-2 chemistry, Receptors, Adrenergic, beta-2 metabolism, Receptors, Adrenergic, beta-2 ultrastructure, Receptors, G-Protein-Coupled chemistry, Receptors, G-Protein-Coupled ultrastructure, Receptors, Vasopressin chemistry, Receptors, Vasopressin metabolism, Receptors, Vasopressin ultrastructure, beta-Arrestins chemistry, beta-Arrestins ultrastructure, GTP-Binding Proteins metabolism, Receptors, G-Protein-Coupled metabolism, Signal Transduction, beta-Arrestins metabolism
- 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 (β2 V2 R). 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
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