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

Nat Struct Mol Biol. 2019 Dec;26(12):1123-1131. doi: 10.1038/s41594-019-0330-y. Epub 2019 Nov 18.

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 β2-adrenergic receptor with the C-terminal tail of the arginine vasopressin type 2 receptor (β2V2R). 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cattle
  • Cryoelectron Microscopy
  • Endosomes / metabolism
  • GTP-Binding Proteins / chemistry
  • GTP-Binding Proteins / metabolism*
  • 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 / metabolism*
  • Receptors, G-Protein-Coupled / ultrastructure
  • Receptors, Vasopressin / chemistry
  • Receptors, Vasopressin / metabolism
  • Receptors, Vasopressin / ultrastructure
  • Signal Transduction*
  • beta-Arrestins / chemistry
  • beta-Arrestins / metabolism*
  • beta-Arrestins / ultrastructure

Substances

  • Receptors, Adrenergic, beta-2
  • Receptors, G-Protein-Coupled
  • Receptors, Vasopressin
  • arginine vasopressin receptor 2, human
  • beta-Arrestins
  • GTP-Binding Proteins