Selective inhibition of Ras interaction with its particular effector by synthetic peptides corresponding to the Ras effector region.

The Journal of Biological Chemistry
M OhnishiT Kataoka

Abstract

Ras proteins possess multiple downstream effectors of distinct structures. We and others demonstrated that Ha-Ras carrying certain effector region mutations could interact differentially with its effectors, implying that significant differences exist in their Ras recognition mechanisms. Here, by employing the fluorescence polarization method, we measured the activity of effector region synthetic peptides bearing various amino acid substitutions to inhibit association of Ras with the effectors human Raf-1 and Schizosaccharomyces pombe Byr2. The effect of these peptides on association with another effector Saccharomyces cerevisiae adenylyl cyclase was also examined by measuring inhibition of the Ras-dependent adenylyl cyclase activity. The peptide corresponding to the residues 17-44 competitively inhibited Ras association with all the three effectors at the Ki values of 1 approximately 10 microM, and the inhibition was considerably attenuated by the D38A mutation. The peptide with the D38N mutation inhibited association of Ha-Ras with Byr2 but not with the others, whereas that with the P34G mutation inhibited association of Ha-Ras with Raf-1 and Byr2 but not with adenylyl cyclase. Thus, the specificity observed with the whole Ras...Continue Reading

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Citations

May 18, 2000·Biochemical and Biophysical Research Communications·H SendohT Kataoka
Jul 2, 2003·Amino Acids·Y L Janin
Feb 10, 2012·Current Pharmaceutical Design·Lu ChenShuxing Zhang
Oct 22, 2008·Biochemical and Biophysical Research Communications·Hideo NonakaKen-Ichi Kariya
Dec 1, 2000·Angewandte Chemie·Alfred Wittinghofer, Herbert Waldmann
Jul 11, 2000·The Journal of Biological Chemistry·M FridmanA Burgess

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