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Science 14 December 2007:
Vol. 318. no. 5857, pp. 1744 - 1748
DOI: 10.1126/science.1150799
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Research Articles

The Structure of a Human p110{alpha}/p85{alpha} Complex Elucidates the Effects of Oncogenic PI3K{alpha} Mutations

Chuan-Hsiang Huang,1,3 Diana Mandelker,2 Oleg Schmidt-Kittler,2 Yardena Samuels,2* Victor E. Velculescu,2 Kenneth W. Kinzler,2 Bert Vogelstein,2{dagger} Sandra B. Gabelli,1{dagger} L. Mario Amzel1{dagger}

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}.

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.

* Present address: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.

{dagger} To whom correspondence should be addressed. E-mail: mamzel{at}jhmi.edu (L.M.A.); gabelli{at}jhmi.edu (S.B.G.); vogelbe{at}jhmi.edu (B.V.)

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Science. ISSN 0036-8075 (print), 1095-9203 (online)