Insight into the mechanism of allosteric activation of PI3Kα by oncoprotein K-Ras4B
Insight into the mechanism of allosteric activation of PI3Kα by oncoprotein K-Ras4B
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深入了解癌蛋白 K-Ras4B 变构激活 PI3K α 的机制
DOI：
10.1016/j.ijbiomac.2019.12.020
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发表时间：
2020-02-01
影响因子：
8.2
通讯作者：
Lu, Shaoyong
中科院分区：
文献类型：
--
作者：
Li, Xinyi;Dai, Jinyuan;Lu, Shaoyong
Ras是小G蛋白超家族的重要成员。Ras在外源性信号的作用下，在GTP结合的活性状态和GDP结合的非活性状态之间转换，在各种信号转导途径中充当二元开关。其下游效应子之一是磷脂酰肌醇-4，5-二磷酸3-激酶a（PI 3 K α），其在PI 3 K/Akt/mTOR通路中将磷脂酰肌醇-4，5-二磷酸化为磷脂酰肌醇-3，4，5-三磷酸，并介导一系列重要的细胞活性，包括细胞生长、迁移和存活。Ras亚型K-Ras 4 B诱导的PI 3 K α的过度激活已被揭示为胰腺导管腺癌肿瘤发生过程中的关键事件，但K-Ras 4 B如何变构激活PI 3 K α的潜在机制仍在很大程度上未得到解决。本文采用加速分子动力学模拟和变构途径分析的方法，探讨了K-Ras 4 B对PI 3 K α的激活过程，并揭示了其潜在的结构机制。我们发现K-Ras 4 B结合诱导了PI 3 K α内更多的构象动力学，并触发了其从自抑制状态向激活状态的逐步转变。此外，K-Ras 4 B的结合显著破坏了p110/p85界面上沿着的相互作用，尤其是p85中的nSH 2与p110中的邻近功能结构域如C2、螺旋结构域和激酶结构域之间的相互作用。改变的结构域间相互作用暴露了激酶结构域，这促进了PI 3 K α的膜结合和底物磷酸化，从而促进了其活化。特别是，社区网络和变构通路分析进一步揭示，在PI 3 K α/K-Ras 4 B系统中，调节p110/p85相互作用的变构信号从螺旋结构域重新连接到激酶结构域，并且几个重要的残基及其相关的介导PI 3 K α自身抑制的变构通路被绕过。所获得的结构机制提供了深入的机制洞察PI 3 K α的变构激活K-Ras 4 B，以及阐明其药物发现。(C)2019由Elsevier B. V.出版
Ras is a key member in the superfamily of small GTPase. Transforming between GTP-bound active state and GDP-bound inactive state in response to exogenous signals, Ras serves as a binary switch in various signaling pathways. One of its downstream effectors is phosphatidylinositol-4,5-bisphosphate 3-kinase a (PI3K alpha), which phosphorylates phosphatidylinositol 4,5-bisphosphate into phosphatidylinositol 3,4,5-trisphosphate in the PI3K/Akt/mTOR pathway and mediates an array of important cellular activities including cell growth, migration and survival. Hyperactivation of PI3K alpha induced by the Ras isoform K-Ras4B has been unveiled as a key event during the oncogenesis of pancreatic ductal adenocarcinoma, but the underlying mechanism of how K-Ras4B allosterically activates PI3K alpha still remains largely unsolved. Here, we employed accelerated molecular dynamic simulations and allosteric pathway analysis to explore into the activation process of PI3K alpha by K-Ras4B and unraveled the underlying structural mechanisms. We found that K-Ras4B binding induced more conformational dynamics within PI3K alpha and triggered its step-wise transition from a self-inhibited state towards an activated state. Moreover, K-Ras4B binding markedly disrupted the interactions along the p110/p85 interface, especially the ones between nSH2 in p85 and its nearby functional domains in p110 like C2, helical, and kinase domains. The altered inter-domain interactions exposed the kinase domain, which promoted the membrane association and substrate phosphorylation of PI3K alpha, thereby facilitating its activation. In particular, the community networks and allosteric pathways analysis further revealed that in PI3K alpha/K-Ras4B system, allosteric signaling regulating p110/p85 interaction was rewired from the helical domain to the kinase domain and several important residues and their related allosteric pathways mediating PI3K alpha autoinhibition were bypassed. The obtained structural mechanisms provide an in-depth mechanistic insight into the allosteric activation of PI3K alpha by K-Ras4B as well as shed light on its drug discovery. (C) 2019 Published by Elsevier B.V.