Pivotal role of extended linker 2 in the activation of Gα by G protein-coupled receptor

Jianyun Huang, Yutong Sun, J. Jillian Zhang, Xin Yun Huang

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 β23 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.

Original languageEnglish (US)
Pages (from-to)272-283
Number of pages12
JournalJournal of Biological Chemistry
Volume290
Issue number1
DOIs
StatePublished - Jan 2 2015

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G-Protein-Coupled Receptors
Chemical activation
GTP-Binding Proteins
Heterotrimeric GTP-Binding Proteins
ras Proteins
Guanine Nucleotides
GTP Phosphohydrolases
Mutant Proteins
Hinges
Biological Products
Adrenergic Receptors
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Pivotal role of extended linker 2 in the activation of Gα by G protein-coupled receptor. / Huang, Jianyun; Sun, Yutong; Jillian Zhang, J.; Huang, Xin Yun.

In: Journal of Biological Chemistry, Vol. 290, No. 1, 02.01.2015, p. 272-283.

Research output: Contribution to journalArticle

Huang, Jianyun ; Sun, Yutong ; Jillian Zhang, J. ; Huang, Xin Yun. / Pivotal role of extended linker 2 in the activation of Gα by G protein-coupled receptor. In: Journal of Biological Chemistry. 2015 ; Vol. 290, No. 1. pp. 272-283.
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