The structure of a human p110α/p85α complex elucidates the effects of oncogenic PI3Kα mutations

PIK3CA, one of the two most frequently mutated oncogenes in human tumors, codes for p110 alpha, the catalytic subunit of a phosphatidylinositol 3- kinase, isoform alpha ( PI3K alpha, p110 alpha/p85). Here, we report a 3.0 angstrom resolution structure of a complex between p110 alpha and a polypeptide containing the p110 alpha- binding domains of p85 alpha, a protein required for its enzymatic activity. The structure shows that many of the mutations occur at residues lying at the interfaces between p110 alpha and p85 alpha or between the kinase domain of p110 alpha and other domains within the catalytic subunit. Disruptions of these interactions are likely to affect the regulation of kinase activity by p85 or the catalytic activity of the enzyme, respectively. In addition to providing new insights about the structure of PI3K alpha, these results suggest specific mechanisms for the effect of oncogenic mutations in p110 alpha and p85 alpha.