Structural Basis of Effector Regulation and Signal Termination in Heterotrimeric Gα Proteins

Stephen R. Sprang, Zhe Chen, Xinlin Du

Research output: Contribution to journalArticle

70 Scopus citations

Abstract

This chapter addresses, from a molecular structural perspective gained from examination of x-ray crystallographic and biochemical data, the mechanisms by which GTP-bound Gα subunits of heterotrimeric G proteins recognize and regulate effectors. The mechanism of GTP hydrolysis by Gα and rate acceleration by GAPs are also considered. The effector recognition site in all Gα homologues is formed almost entirely of the residues extending from the C-terminal half of α2 (Switch II) together with the α3 helix and its junction with the β5 strand. Effector binding does not induce substantial changes in the structure of Gα•GTP. Effectors are structurally diverse. Different effectors may recognize distinct subsets of effector-binding residues of the same Gα protein. Specificity may also be conferred by differences in the main chain conformation of effector-binding regions of Gα subunits. Several Gα regulatory mechanisms are operative. In the regulation of GMP phospodiesterase, Gαt sequesters an inhibitory subunit. Gαs is an allosteric activator and inhibitor of adenylyl cyclase, and Gαi is an allosteric inhibitor. Gαq does not appear to regulate GRK, but is rather sequestered by it. GTP hydrolysis terminates the signaling state of Gα. The binding energy of GTP that is used to stabilize the Gα:effector complex is dissipated in this reaction. Chemical steps of GTP hydrolysis, specifically, formation of a dissociative transition state, is rate limiting in Ras, a model G protein GTPase, even in the presence of a GAP; however, the energy of enzyme reorganization to produce a catalytically active conformation appears to be substantial. It is possible that the collapse of the switch regions, associated with Gα deactivation, also encounters a kinetic barrier, and is coupled to product (Pi) release or an event preceding formation of the GDP•Pi complex. Evidence for a catalytic intermediate, possibly metaphosphate, is discussed. Gα GAPs, whether exogenous proteins or effector-linked domains, bind to a discrete locus of Gα that is composed of Switch I and the N-terminus of Switch II. This site is immediately adjacent to, but does not substantially overlap, the Gα effector binding site. Interactions of effectors and exogenous GAPs with Gα proteins can be synergistic or antagonistic, mediated by allosteric interactions among the three molecules. Unlike GAPs for small GTPases, Gα GAPs supply no catalytic residues, but rather appear to reduce the activation energy for catalytic activation of the Gα catalytic site.

Original languageEnglish (US)
Pages (from-to)1-65
Number of pages65
JournalAdvances in Protein Chemistry
Volume74
DOIs
StatePublished - 2007

ASJC Scopus subject areas

  • Biochemistry

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