Molecular architecture of Gαo and the structural basis for RGS16-mediated deactivation

Kevin C. Slep, Michele A. Kercher, Thomas Wieland, Ching Kang Chen, Melvin I. Simon, Paul B. Sigler

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

Heterotrimeric G proteins relay extracellular cues from heptahelical transmembrane receptors to downstream effector molecules. Composed of an α subunit with intrinsic GTPase activity and a βγ heterodimer, the trimeric complex dissociates upon receptor-mediated nucleotide exchange on the α subunit, enabling each component to engage downstream effector targets for either activation or inhibition as dictated in a particular pathway. To mitigate excessive effector engagement and concomitant signal transmission, the Gα subunit's intrinsic activation timer (the rate of GTP hydrolysis) is regulated spatially and temporally by a class of GTPase accelerating proteins (GAPs) known as the regulator of G protein signaling (RGS) family. The array of G protein-coupled receptors, Gα subunits, RGS proteins and downstream effectors in mammalian systems is vast. Understanding the molecular determinants of specificity is critical for a comprehensive mapping of the G protein system. Here, we present the 2.9 Å crystal structure of the enigmatic, neuronal G protein Gαo in the GTP hydrolytic transition state, complexed with RGS16. Comparison with the 1.89 Å structure of apo-RGS16, also presented here, reveals plasticity upon Gαo binding, the determinants for GAP activity, and the structurally unique features of Gαo that likely distinguish it physiologically from other members of the larger Gαi family, affording insight to receptor, GAP and effector specificity.

Original languageEnglish (US)
Pages (from-to)6243-6248
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number17
DOIs
StatePublished - Apr 29 2008
Externally publishedYes

Keywords

  • G protein
  • GAP
  • RGS

ASJC Scopus subject areas

  • General

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