Pivotal role of extended linker 2 in the activation of Gα by G protein-coupled receptor. Academic Article uri icon

Overview

abstract

  • G protein-coupled receptors (GPCRs) relay extracellular signals mainly to heterotrimeric G-proteins (Gαβγ) and they are the most successful drug targets. The mechanisms of G-protein activation by GPCRs are not well understood. Previous studies have revealed a signal relay route from a GPCR via the C-terminal α5-helix of Gα to the guanine nucleotide-binding pocket. Recent structural and biophysical studies uncover a role for the opening or rotating of the α-helical domain of Gα during the activation of Gα by a GPCR. Here we show that β-adrenergic receptors activate eight Gαs mutant proteins (from a screen of 66 Gαs mutants) that are unable to bind Gβγ subunits in cells. Five of these eight mutants are in the αF/Linker 2/β2 hinge region (extended Linker 2) that connects the Ras-like GTPase domain and the α-helical domain of Gαs. This extended Linker 2 is the target site of a natural product inhibitor of Gq. Our data show that the extended Linker 2 is critical for Gα activation by GPCRs. We propose that a GPCR via its intracellular loop 2 directly interacts with the β2/β3 loop of Gα to communicate to Linker 2, resulting in the opening and closing of the α-helical domain and the release of GDP during G-protein activation.

publication date

  • November 20, 2014

Research

keywords

  • GTP-Binding Protein alpha Subunits, Gs
  • GTP-Binding Protein beta Subunits
  • GTP-Binding Protein gamma Subunits
  • Receptors, Adrenergic, beta

Identity

PubMed Central ID

  • PMC4281731

Scopus Document Identifier

  • 84920517379

Digital Object Identifier (DOI)

  • 10.1074/jbc.M114.608661

PubMed ID

  • 25414258

Additional Document Info

volume

  • 290

issue

  • 1