Specific Substates of Ras To Interact with GAPs and Effectors: Revealed by Theoretical Simulations and FTIR Experiments.
Specific Substates of Ras To Interact with GAPs and Effectors: Revealed by Theoretical Simulations and FTIR Experiments.
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Ras 与 GAP 和效应器相互作用的特定亚态：理论模拟和 FTIR 实验揭示
DOI：
10.1021/acs.jpclett.8b00342
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发表时间：
2018-03-15
期刊：
影响因子：
--
通讯作者：
Gerwert K
中科院分区：
文献类型：
--
作者：
Li Y;Zhang Y;Großerüschkamp F;Stephan S;Cui Q;Kötting C;Xia F;Gerwert K
致癌Ras蛋白采用各种特定构象状态来执行其信号转导功能。 X射线和NMR实验获得的大量Ras结构说明了Ras采用的不同构象。然而，很难将特定的结构特征与 Ras 函数联系起来。在这项工作中，我们基于广泛的显式溶剂模拟报告了 Ras∙GTP 的自由能景观。自由能图清楚地表明 Ras∙GTP 的功能状态 2 实际上有两个不同的子状态，此处表示为“Tyr32in”和“Tyr32out”。无偏 MD 模拟表明，两种底物在溶液中以亚微秒尺度相互转化，指出 Ras∙GTP 选择性与 GAP 和效应器相互作用的新机制。这一提议得到了时间分辨 FTIR 实验的进一步支持，该实验证明 Tyr32 使 Ras·GAP 复合物不稳定并促进 Ras 信号传导的有效终止。 Ras采用Tyr32in和Tyr32out分别与效应器和GAP相互作用。
The oncogenic Ras protein adopts various specific conformational states to execute its function in signal transduction. The large number of Ras structures obtained from X-ray and NMR experiments illustrate the diverse conformations that Ras adopts. It is difficult, however, to connect specific structural features with Ras functions. In this work, we report free energy landscape of Ras∙GTP based on extensive explicit solvent simulations. The free energy map clearly shows that the functional state 2 of Ras∙GTP in fact has two distinct substates, denoted here as “Tyr32in” and “Tyr32out”. Unbiased MD simulations show that the two substrates interconvert on the sub-microsecond scale in solution, pointing to a novel mechanism for Ras∙GTP to selectively interact with GAPs and effectors. This proposal is further supported by time-resolved FTIR experiments, which demonstrate that Tyr32 destabilizes the Ras·GAP complex and facilitates an efficient termination of Ras signaling. Ras adopts Tyr32in and Tyr32out to interact with effector and GAP respectively.
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影响因子：
2.9
作者：
Cepus, V;Scheidig, AJ;Gerwert, K
通讯作者：
Gerwert, K
影响因子：
5.5
作者：
Hess, Berk;Kutzner, Carsten;Lindahl, Erik
通讯作者：
Lindahl, Erik
影响因子：
3.2
作者：
Koetting, Carsten;Kallenbach, Angela;Gerwert, Klaus
通讯作者：
Gerwert, Klaus
影响因子：
4.3
作者：
Lukman, Suryani;Grant, Barry J.;McCammon, J. Andrew
通讯作者：
McCammon, J. Andrew
DOI：
10.1073/pnas.131549798
发表时间：
2001-07-03
影响因子：
11.1
作者：
Allin, C;Ahmadian, MR;Gerwert, K
通讯作者：
Gerwert, K