Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase gamma.
Ras activation of phosphoinositide 3-kinase (PI3K) is important for survival of transformed cells. We find that PI3Kgamma is strongly and directly activated by H-Ras G12V in vivo or by GTPgammaS-loaded H-Ras in vitro. We have determined a crystal structure of a PI3Kgamma/Ras.GMPPNP complex. A critical loop in the Ras binding ... domain positions Ras so that it uses its switch I and switch II regions to bind PI3Kgamma. Mutagenesis shows that interactions with both regions are essential for binding PI3Kgamma. Ras also forms a direct contact with the PI3Kgamma catalytic domain. These unique Ras/PI3Kgamma interactions are likely to be shared by PI3Kalpha. The complex with Ras shows a change in the PI3K conformation that may represent an allosteric component of Ras activation.
Mesh Terms:
1-Phosphatidylinositol 3-Kinase, Animals, Binding Sites, COS Cells, Crystallography, X-Ray, Guanosine 5'-O-(3-Thiotriphosphate), Humans, Isoenzymes, Kinetics, Models, Molecular, Mutagenesis, Site-Directed, Neutrophils, Protein Binding, Protein Conformation, Protein Structure, Tertiary, ras Proteins
1-Phosphatidylinositol 3-Kinase, Animals, Binding Sites, COS Cells, Crystallography, X-Ray, Guanosine 5'-O-(3-Thiotriphosphate), Humans, Isoenzymes, Kinetics, Models, Molecular, Mutagenesis, Site-Directed, Neutrophils, Protein Binding, Protein Conformation, Protein Structure, Tertiary, ras Proteins
Cell
Date: Dec. 08, 2000
PubMed ID: 11136978
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