The Structure of a Human p110a/p85a Complex Elucidates the Effects of Oncogenic PI3Ka Mutations

PIK3CA, one of the two most frequently mutated oncogenes in human tumors, codes for p110a, the catalytic subunit of a phosphatidylinositol 3-kinase, isoform a (PI3Ka, p110a/p85). Here, we report a 3.0 angstrom resolution structure of a complex between p110a and a polypeptide containing the p110a-binding domains of p85a, a protein required for its enzymatic activity. The structure shows that many of the mutations occur at residues lying at the interfaces between p110a and p85a or between the kinase domain of p110a 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 PI3Ka, these results suggest specific mechanisms for the effect of oncogenic mutations in p110a and p85a.