The Structure of a Human p110α/p85α Complex Elucidates the Effects of Oncogenic PI3Kα Mutations

Author:

Huang Chuan-Hsiang123,Mandelker Diana123,Schmidt-Kittler Oleg123,Samuels Yardena123,Velculescu Victor E.123,Kinzler Kenneth W.123,Vogelstein Bert123,Gabelli Sandra B.123,Amzel L. Mario123

Affiliation:

1. Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

2. Ludwig Center for Cancer Genetics and Therapeutics, and Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.

3. Graduate Program in Immunology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Abstract

PIK3CA , one of the two most frequently mutated oncogenes in human tumors, codes for p110α, the catalytic subunit of a phosphatidylinositol 3-kinase, isoform α (PI3Kα, p110α/p85). Here, we report a 3.0 angstrom resolution structure of a complex between p110α and a polypeptide containing the p110α-binding domains of p85α, a protein required for its enzymatic activity. The structure shows that many of the mutations occur at residues lying at the interfaces between p110α and p85α or between the kinase domain of p110α 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 PI3Kα, these results suggest specific mechanisms for the effect of oncogenic mutations in p110α and p85α.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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