Molecular dynamics reveal a novel kinase-substrate interface that regulates protein translation.
Molecular dynamics reveal a novel kinase-substrate interface that regulates protein translation.
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分子动力学揭示了一种调节蛋白质翻译的新型激酶-底物界面。
DOI：
10.1093/jmcb/mju044
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Sadler AJ.
中科院分区：
文献类型：
--
作者：
Liu MS;Wang D;Morimoto H;Yim HC;Irving AT;Williams BR;Sadler AJ.
基因表达的一个关键控制点是蛋白质翻译的起始，真核起始因子2α（eIF2α）的抑制性磷酸化构成了普遍的应激反应。在人类中，四种激酶感知不同的生理应激以调节eIF2α来控制细胞分化、适应和存活。在这里，我们开发了一个计算分子模型eIF2α和它的激酶之一，蛋白激酶R，模拟他们的相互作用的动力学。粗粒度动力学模拟产生的预测提出了一种新的行动模式。实验证实了这些预测，确定了蛋白质复合物中以前未被识别的界面，该界面由eIF2α及其激酶中的动态残基组成，这些残基对调节蛋白质翻译至关重要。这些发现要求重新解释eIF2α激酶的当前作用机制，并证明进行计算分析以评估蛋白质功能的价值。
A key control point in gene expression is the initiation of protein translation, with a universal stress response being constituted by inhibitory phosphorylation of the eukaryotic initiation factor 2α (eIF2α). In humans, four kinases sense diverse physiological stresses to regulate eIF2α to control cell differentiation, adaptation, and survival. Here we develop a computational molecular model of eIF2α and one of its kinases, the protein kinase R, to simulate the dynamics of their interaction. Predictions generated by coarse-grained dynamics simulations suggest a novel mode of action. Experimentation substantiates these predictions, identifying a previously unrecognized interface in the protein complex, which is constituted by dynamic residues in both eIF2α and its kinases that are crucial to regulate protein translation. These findings call for a reinterpretation of the current mechanism of action of the eIF2α kinases and demonstrate the value of conducting computational analysis to evaluate protein function.