Structural basis of activity and subunit recognition in G protein heterotrimers

Mark A. Wall, Bruce A. Posner, Stephen R. Sprang

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83 Scopus citations


Background: Inactive heterotrimeric G proteins are composed of a GDP-bound α subunit (G(α)) and a stable heterodimer of G(β) and G(γ) subunits. Upon stimulation by a receptor, G(α) subunits exchange GDP for GTP and dissociate from G(βγ) both G(α) and G(βγ) then interact with downstream effectors. Isoforms of G(α), G(β) and G(γ) potentially give rise to many heterotrimeric combinations, limited in part by amino acid sequence differences that lead to selective interactions. The mechanism by which GTP promotes G(βγ) dissociation is incompletely understood. The Gly203→Ala mutant of G(iα1) binds and hydrolyzes GTP normally but does not dissociate from G(βγ) demonstrating that GTP binding and activation can be uncoupled. Structural data are therefore important for understanding activation and subunit recognition in G protein heterotrimers. Results: The structures of the native (G(iα1β1γ2)) heterotrimer and that formed with Gly203→AlaG(iα1) have been determined to resolutions of 2.3 Å, and 2.4 Å, respectively, and reveal previously unobserved segments at the G(γ2) C terminus. The Gly203→Ala mutation alters the conformation of the N terminus of the switch II region (Val201-Ala203), but not the global structure of the heterotrimer. The N termini of G(β) and G(γ) form a rigid coiled coil that packs at varying angles against the β propeller of G(β). Conformational differences in the CD loop of β blade 2 of G(β) mediate isoform-specific contacts with G(α). Conclusions: The Gly203→Ala mutation in G(iα1) blocks the conformational changes in switch II that are required to release G(βγ) upon binding GTP. The interface between the ras-like domain of G, and the β propeller of G(β) appears to be conserved in all G protein heterotrimers. Sequence variation at the G(β)-G(α) interface between the N-terminal helix of G(α) and the CD loop of β blade 2 of G(β1) (residues 127-135) could mediate isoform-specific contacts. The specificity of G(β) and Gγ interactions is largely determined by sequence variation in the contact region between helix 2 of Gγ and the surface of G(β).

Original languageEnglish
Pages (from-to)1169-1183
Number of pages15
Issue number9
StatePublished - Sep 15 1998


  • GTP-binding proteins
  • Protein conformation
  • Protein structure
  • Signal transduction
  • X-ray crystallography


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