AN INTRINSIC GUANINE-NUCLEOTIDE EXCHANGE INHIBITOR IN G(I2)ALPHA - SIGNIFICANCE OF G-PROTEIN SELF-SUPPRESSION WHICH ANTAGONIZES RECEPTOR SIGNAL

The alpha subunit of G(i2) (G(i2)alpha) is a member of the heterotrime ric G protein family, which transduces receptor signals as a proto-onc ogene product. We have found a novel self-suppressive region in G(i2)a lpha near its C terminus. A polypeptide consisting of residues 338-352 of G(i2)alpha (G(i2)alpha-338-352) antagonizes receptor- and receptor peptide stimulated G(i2)alpha activation, without affecting basal act ivity. Antagonism by G(i2)alpha-338-352 is attributable to an interact ion with activated G(i2)alpha, which is not competitive with receptor polypeptides. Combined with the reports suggesting the presence of sel f-suppressive domains in a juxta-C-terminal portion of G(i2)alpha and G(o) alpha, this study sup ports the hypothesis that G(i2)alpha-338-35 2 constitutes an intrinsic guanine nucleotide exchange inhibitor, whic h in turn antagonizes receptor stimulation, suggesting that G proteins are activated by receptors through relaxation of a self suppressive c onformation.