Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit
Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit
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DOI：
10.1126/science.1135394
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发表时间：
2007-07-13
期刊：
影响因子：
56.9
通讯作者：
Williams, Roger L.
中科院分区：
文献类型：
--
作者：
Miled, Nabil;Yan, Ying;Williams, Roger L.
许多人类癌症涉及磷酸肌醇3-激酶PI 3 K α的上调，在p110 α催化亚基和p85 α调节亚基中鉴定出致癌突变。我们使用晶体学和生物化学的方法来深入了解激活突变的两个非催化p110 α结构域的衔接子结合和螺旋结构域。p110 α与p85 α Src间同源性2（间SH 2）结构域复合物中p110 α的衔接子结合结构域的结构表明，衔接子结合结构域中的致癌突变不在间SH 2界面，而是在极性表面补丁中，该补丁是holo p110/p85复合物中其他结构域的合理对接位点。我们还检查了螺旋结构域突变，发现Glu（545）到Lys（545）（E545 K）致癌突变体破坏了与p85 N-末端SH 2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PI 3 Ks结构的理解，并深入了解了导致功能增加的两类突变如何导致癌症。
Many human cancers involve up-regulation of the phosphoinositide 3-kinase PI3K alpha, with oncogenic mutations identified in both the p110 alpha catalytic and the p85 alpha regulatory subunits. We used crystallographic and biochemical approaches to gain insight into activating mutations in two noncatalytic p110 alpha domains-the adaptor-binding and the helical domains. A structure of the adaptor-binding domain of p110 alpha in a complex with the p85 alpha 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 Glu(545) to Lys(545) (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.