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

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Nature Structural and Molecular Biology. 2019 Dec 26;26(12):1123-1131. doi: 10.1038/s41594-019-0330-y

Nguyen AH, Thomsen AR, Cahill TJ, Huang R, Huang L, 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, Chen X, Sunahara R, Steyaert J, Molina H, Yu Z, Georges A, Lefkowitz RJ

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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-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.

PMID: 31740855 [PubMed - indexed for MEDLINE]

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

Abstract

PMID: 31740855 [PubMed - indexed for MEDLINE]

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