The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations.
PIK3CA, one of the two most frequently mutated oncogenes in human tumors, codes for p110alpha, the catalytic subunit of a phosphatidylinositol 3-kinase, isoform alpha (PI3Kalpha, p110alpha/p85). Here, we report a 3.0 angstrom resolution structure of a complex between p110alpha and a polypeptide containing the p110alpha-binding domains of p85alpha, a protein required for its enzymatic activity. The structure shows that many of the mutations occur at residues lying at the interfaces between p110alpha and p85alpha or between the kinase domain of p110alpha 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 PI3Kalpha, these results suggest specific mechanisms for the effect of oncogenic mutations in p110alpha and p85alpha.
Huang
Chuan-Hsiang
CH
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Mandelker
Diana
D
Schmidt-Kittler
Oleg
O
Samuels
Yardena
Y
Velculescu
Victor E
VE
Kinzler
Kenneth W
KW
Vogelstein
Bert
B
Gabelli
Sandra B
SB
Amzel
L Mario
LM
D000255:Adenosine Triphosphate; D000595:Amino Acid Sequence; D001665:Binding Sites; D020134:Catalytic Domain; D058534:Class I Phosphatidylinositol 3-Kinases; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018909:src Homology Domains
D021122:Protein Subunits; D000255:Adenosine Triphosphate; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human