The N-terminal domain of RGS4 confers receptor-selective inhibition of G protein signaling.
Regulators of heterotrimeric G protein signaling (RGS) proteins are GTPase-activating proteins (GAPs) that accelerate GTP hydrolysis by Gq and Gi alpha 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 10(4)-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 Galphaq 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.
Zeng
W
W
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.
Xu
X
X
Popov
S
S
Mukhopadhyay
S
S
Chidiac
P
P
Swistok
J
J
Danho
W
W
Yagaloff
K A
KA
Fisher
S L
SL
Ross
E M
EM
Muallem
S
S
Wilkie
T M
TM
D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002217:Carbachol / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006868:Hydrolysis; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D020710:RGS Proteins; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017384:Sequence Deletion
D010446:Peptide Fragments; D011506:Proteins; D020710:RGS Proteins; D011956:Receptors, Cell Surface; C098799:RGS4 protein; D002217:Carbachol; D019204:GTP-Binding Proteins; D002118:Calcium