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The Structure of a Human p110/p85 Complex Elucidates the Effects of Oncogenic PI3K Mutations
Chuan-Hsiang Huang,1,3Diana Mandelker,2Oleg Schmidt-Kittler,2Yardena Samuels,2*Victor E. Velculescu,2Kenneth W. Kinzler,2Bert Vogelstein,2Sandra B. Gabelli,1L. Mario Amzel1
PIK3CA, one of the two most frequently mutated oncogenes inhuman tumors, codes for p110, the catalytic subunit of a phosphatidylinositol3-kinase, isoform (PI3K, p110/p85). Here, we report a 3.0 angstromresolution structure of a complex between p110 and a polypeptidecontaining the p110-binding domains of p85, a protein requiredfor its enzymatic activity. The structure shows that many ofthe mutations occur at residues lying at the interfaces betweenp110 and p85 or between the kinase domain of p110 and otherdomains within the catalytic subunit. Disruptions of these interactionsare likely to affect the regulation of kinase activity by p85or the catalytic activity of the enzyme, respectively. In additionto providing new insights about the structure of PI3K, theseresults suggest specific mechanisms for the effect of oncogenicmutations in p110 and p85.
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, NationalInstitutes of Health, Bethesda, MD 20892, USA.
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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/p85
, the catalytic subunit of a phosphatidylinositol 3-kinase, isoform 
To whom correspondence should be addressed. E-mail: 
