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

TitleStructure of an endosomal signaling GPCR-G protein-β-arrestin megacomplex.
Publication TypeJournal Article
Year of Publication2019
AuthorsNguyen, A. H., A. R. B. Thomsen, T. J. Cahill, R. Huang, L-Y. Huang, T. Marcink, O. B. Clarke, S. Heissel, A. Masoudi, D. Ben-Hail, F. Samaan, V. P. Dandey, Y. Zi Tan, C. Hong, J. P. Mahoney, S. Triest, J. Little, X. Chen, R. Sunahara, J. Steyaert, H. Molina, Z. Yu, A. des Georges, and R. J. Lefkowitz
JournalNat Struct Mol Biol
Date Published2019 Dec

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

Alternate JournalNat. Struct. Mol. Biol.
PubMed ID31740855
Grant ListP41 GM103310 / GM / NIGMS NIH HHS / United States
P41 GM103314 / GM / NIGMS NIH HHS / United States
P41 GM109824 / GM / NIGMS NIH HHS / United States
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