Palmitoylation of the α subunit of the guanine nucleotide-binding protein G(z) inhibited by more than 90 percent its response to the guanosine triphosphatase (GTPase)-accelerating activity of G(z) GAP, a G(z)-selective member of the regulators of G-protein signaling (RGS) protein family of GTPase-activating proteins (GAPs). Palmitoylation both decreased the affinity of G(z) GAP for the GTP-bound form of Gα(z) by at least 90 percent and decreased the maximum rate of GTP hydrolysis. Inhibition was reversed by removal of the palmitoyl group by dithiothreitol. Palmitoylation of Gα(z) also inhibited its response to the GAP activity of Gα-interacting Protein (GAIP), another RGS protein, and palmitoylation of Gα(l1) inhibited its response to RGS4. The extent of inhibition of G(z) GAP, GAIP, RGS4, and RGS10 correlated roughly with their intrinsic GAP activities for the Gα target used in the assay. Reversible palmitoylation is thus a major determinant of G(z) deactivation after its stimulation by receptors, and may be a general mechanism for prolonging or potentiating G-protein signaling.
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