Miled Nabil, Yan Ying, Hon Wai-Ching, Perisic Olga, Zvelebil Marketa, Inbar Yuval, Schneidman-Duhovny Dina, Wolfson Haim J, Backer Jonathan M, Williams Roger L
Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK.
Science. 2007 Jul 13;317(5835):239-42. doi: 10.1126/science.1135394.
Many human cancers involve up-regulation of the phosphoinositide 3-kinase PI3Kalpha, with oncogenic mutations identified in both the p110alpha catalytic and the p85alpha regulatory subunits. We used crystallographic and biochemical approaches to gain insight into activating mutations in two noncatalytic p110alpha domains-the adaptor-binding and the helical domains. A structure of the adaptor-binding domain of p110alpha in a complex with the p85alpha inter-Src homology 2 (inter-SH2) domain shows that oncogenic mutations in the adaptor-binding domain are not at the inter-SH2 interface but in a polar surface patch that is a plausible docking site for other domains in the holo p110/p85 complex. We also examined helical domain mutations and found that the Glu545 to Lys545 (E545K) oncogenic mutant disrupts an inhibitory charge-charge interaction with the p85 N-terminal SH2 domain. These studies extend our understanding of the architecture of PI3Ks and provide insight into how two classes of mutations that cause a gain in function can lead to cancer.
许多人类癌症都涉及磷酸肌醇3-激酶PI3Kα的上调，在p110α催化亚基和p85α调节亚基中均发现了致癌突变。我们采用晶体学和生化方法来深入了解p110α两个非催化结构域（衔接子结合结构域和螺旋结构域）中的激活突变。p110α衔接子结合结构域与p85α中间Src同源2（inter-SH2）结构域形成的复合物的结构表明，衔接子结合结构域中的致癌突变并非位于inter-SH2界面，而是位于一个极性表面区域，该区域可能是全酶p110/p85复合物中其他结构域的对接位点。我们还研究了螺旋结构域突变，发现谷氨酸545突变为赖氨酸545（E545K）的致癌突变体破坏了与p85 N端SH2结构域的抑制性电荷-电荷相互作用。这些研究扩展了我们对PI3K结构的理解，并深入了解了两类功能获得性突变如何导致癌症。
