TY - JOUR
T1 - The structure of a human p110α/p85α complex elucidates the effects of oncogenic PI3Kα mutations
AU - Huang, Chuan Hsiang
AU - Mandelker, Diana
AU - Schmidt-Kittler, Oleg
AU - Samuels, Yardena
AU - Velculescu, Victor E.
AU - Kinzler, Kenneth W.
AU - Vogelstein, Bert
AU - Gabelli, Sandra B.
AU - Amzel, L. Mario
N1 - Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.
PY - 2007/12/14
Y1 - 2007/12/14
N2 - 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.
AB - 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.
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U2 - 10.1126/science.1150799
DO - 10.1126/science.1150799
M3 - Article
C2 - 18079394
AN - SCOPUS:37249056471
SN - 0036-8075
VL - 318
SP - 1744
EP - 1748
JO - Science
JF - Science
IS - 5857
ER -