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J Biol Chem, Vol. 273, Issue 52, 34687-34690, December 25, 1998
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From the Departments of Regulators of heterotrimeric G protein signaling
(RGS) proteins are GTPase-activating proteins (GAPs) that accelerate
GTP hydrolysis by Gq and Gi Physiology and
¶ Pharmacology, University of Texas Southwestern Medical Center,
Dallas, Texas 75235 and Department of Metabolic Diseases,
Hoffmann-La Roche, Inc., Nutley, New Jersey 07110
subunits,
thus attenuating signaling. Mechanisms that provide more precise
regulatory specificity have been elusive. We report here that an
N-terminal domain of RGS4 discriminated among receptor signaling
complexes coupled via Gq. Accordingly, deletion of the
N-terminal domain of RGS4 eliminated receptor selectivity and reduced
potency by 104-fold. Receptor selectivity and potency of
inhibition were partially restored when the RGS4 box was added together
with an N-terminal peptide. In vitro reconstitution
experiments also indicated that sequences flanking the RGS4 box were
essential for high potency GAP activity. Thus, RGS4 regulates
Gq class signaling by the combined action of two domains:
1) the RGS box accelerates GTP hydrolysis by Gq and 2)
the N terminus conveys high affinity and receptor-selective inhibition.
These activities are each required for receptor selectivity and high
potency inhibition of receptor-coupled Gq signaling.
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