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Vol. 273, Issue 3, 1529-1533, January 16, 1998
From the Department of Cell Biology and Physiology, Washington
University School of Medicine, St. Louis, Missouri 63110
GTP hydrolysis by guanine nucleotide-binding
proteins, an essential step in many biological processes, is stimulated
by GTPase-activating proteins (GAPs). The mechanisms whereby GAPs
stimulate GTP hydrolysis are unknown. We have used mutational,
biochemical, and structural data to investigate how RGS4, a GAP for
heterotrimeric G protein
Mechanism of RGS4, a GTPase-activating Protein for G Protein
Subunits
subunits, stimulates GTP hydrolysis. Many
of the residues of RGS4 that interact with
Gi
1 are important for GAP activity. Furthermore, optimal GAP activity appears to require the additive effects of interactions along the RGS4-G interface.
GAP-defective RGS4 mutants invariably were defective in binding
G subunits in their transition state; furthermore, the
apparent strengths of GAP and binding defects were correlated. Thus,
none of these residues of RGS4, including asparagine 128, the only
residue positioned at the active site of Gi1, is
required exclusively for catalyzing GTP hydrolysis. These results and
structural data (Tesmer, J. G. G., Berman, D. M.,
Gilman, A. G., and Sprang, S. R. (1997) Cell 89, 251-261) indicate that RGS4 stimulates GTP hydrolysis primarily by
stabilizing the transition state conformation of the switch regions of
the G protein, favoring the transition state of the reactants.
Therefore, although monomeric and heterotrimeric G proteins are
related, their GAPs have evolved distinct mechanisms of action.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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