6ni3

Publication Abstract from PubMed

Classically, G-protein-coupled receptors (GPCRs) are thought to activate G protein from the plasma membrane and are subsequently desensitized by beta-arrestin (beta-arr). However, some GPCRs continue to signal through G protein from internalized compartments, mediated by a GPCR-G protein-beta-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 beta-arr to the core and phosphorylated tail, respectively, of a single active human chimeric beta2-adrenergic receptor with the C-terminal tail of the arginine vasopressin type 2 receptor (beta2V2R). All three components adopt their canonical active conformations, suggesting that a single megaplex GPCR is capable of simultaneously activating G protein and beta-arr. Our findings provide a structural basis for GPCR-mediated sustained internalized G protein signaling.

Structure of an endosomal signaling GPCR-G protein-beta-arrestin megacomplex.,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, Lefkowitz RJ Nat Struct Mol Biol. 2019 Nov 18. pii: 10.1038/s41594-019-0330-y. doi:, 10.1038/s41594-019-0330-y. PMID:31740855^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.