Oncogenic Mutations Counteract Intrinsic Disorder in the EGFR Kinase and Promote Receptor Dimerization
Oncogenic Mutations Counteract Intrinsic Disorder in the EGFR Kinase and Promote Receptor Dimerization
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DOI：
10.1016/j.cell.2012.02.063
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发表时间：
2012-05-11
期刊：
影响因子：
64.5
通讯作者：
Shaw, David E.
中科院分区：
文献类型：
--
作者：
Shan, Yibing;Eastwood, Michael P.;Shaw, David E.
表皮生长因子受体（EGFR）的突变和过表达与多种癌症的发展相关，使得这种原型二聚化激活的受体酪氨酸激酶成为癌症药物的突出靶点。使用长时间尺度的分子动力学模拟，我们发现，野生型EGFR激酶结构域的N叶二聚化接口本质上是无序的，它变得有序后，只有二聚化。此外，我们的模拟表明，一些癌症相关的突变远端的二聚化界面，特别是广泛的L834R突变（也称为L858R），通过抑制这种局部疾病促进EGFR二聚化。我们的生物物理学实验和激酶酶分析证实了这些发现，表明L834R突变主要通过促进EGFR二聚化而不是通过允许激活而不二聚化来引起异常高的活性。我们还发现EGFR激酶结构域Tyr845的磷酸化可以抑制内源性疾病，提示自主EGFR信号传导的分子机制。
The mutation and overexpression of the epidermal growth factor receptor (EGFR) are associated with the development of a variety of cancers, making this prototypical dimerization-activated receptor tyrosine kinase a prominent target of cancer drugs. Using long-timescale molecular dynamics simulations, we find that the N lobe dimerization interface of the wild-type EGFR kinase domain is intrinsically disordered and that it becomes ordered only upon dimerization. Our simulations suggest, moreover, that some cancer-linked mutations distal to the dimerization interface, particularly the widespread L834R mutation (also referred to as L858R), facilitate EGFR dimerization by suppressing this local disorder. Corroborating these findings, our biophysical experiments and kinase enzymatic assays indicate that the L834R mutation causes abnormally high activity primarily by promoting EGFR dimerization rather than by allowing activation without dimerization. We also find that phosphorylation of EGFR kinase domain at Tyr845 may suppress the intrinsic disorder, suggesting a molecular mechanism for autonomous EGFR signaling.