Molecular dynamics of the proline switch and its role in Crk signaling.
Molecular dynamics of the proline switch and its role in Crk signaling.
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DOI：
10.1021/jp5013297
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发表时间：
2014-05-01
期刊：
影响因子：
--
通讯作者：
Levy RM
中科院分区：
文献类型：
--
作者：
Xia J;Levy RM
Crk衔接蛋白作为形成蛋白质复合物（包括各种生长和分化因子）的分子计时器发挥核心作用。Crk调控的缺失导致多种癌症。最近提出了Crk的自我调节机制，其涉及结构域-结构域重排。它由特定脯氨酸残基（鸡Crk II中的Pro238）的顺反异构化引发，并可被亲环素A加速。为了了解脯氨酸开关如何在分子水平上控制自抑制，我们进行了大规模的分子动力学和代谢动力学模拟的背景下，短肽和多结构域的鸡Crk II。我们发现，宏观态的平衡和动力学性质不仅受到特定脯氨酸的局部环境的调节，而且还受到多个域的全局组织的调节。我们观察到的两个宏观状态（顺式关闭/自抑制和反式开放/不受抑制）与NMR实验和预测的障碍。我们还提出了一个中间状态，反式封闭状态，有趣的是，据报道，这是一个普遍的状态，在人类Crk II。这种宏状态的存在表明，关闭的自抑制由Cyp A的速率可能是有限的，由这个中间状态的弛豫速率。
The Crk adaptor proteins play a central role as a molecular timer for the formation of protein complexes including various growth and differentiation factors. The loss of regulation of Crk results in many kinds of cancers. A self-regulatory mechanism for Crk was recently proposed, which involves domain–domain rearrangement. It is initiated by a cis–trans isomerization of a specific proline residue (Pro238 in chicken Crk II) and can be accelerated by Cyclophilin A. To understand how the proline switch controls the autoinhibition at the molecular level, we performed large-scale molecular dynamics and metadynamics simulations in the context of short peptides and multidomain constructs of chicken Crk II. We found that the equilibrium and kinetic properties of the macrostates are regulated not only by the local environments of specified prolines but also by the global organization of multiple domains. We observe the two macrostates (cis closed/autoinhibited and trans open/uninhibited) consistent with NMR experiments and predict barriers. We also propose an intermediate state, the trans closed state, which interestingly was reported to be a prevalent state in human Crk II. The existence of this macrostate suggests that the rate of switching off the autoinhibition by Cyp A may be limited by the relaxation rate of this intermediate state.
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DOI：
10.1186/bcr3183
发表时间：
2012-05-08
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Fathers KE;Bell ES;Rajadurai CV;Cory S;Zhao H;Mourskaia A;Zuo D;Madore J;Monast A;Mes-Masson AM;Grosset AA;Gaboury L;Hallet M;Siegel P;Park M
通讯作者：
Park M
影响因子：
2.9
作者：
Aliev, Abil E.;Bhandal, Simrath;Courtier-Murias, Denis
通讯作者：
Courtier-Murias, Denis
影响因子：
3
作者：
Bonomi, M.;Barducci, A.;Parrinello, M.
通讯作者：
Parrinello, M.
影响因子：
15
作者：
Hamelberg, Donald;McCammon, J. Andrew
通讯作者：
McCammon, J. Andrew
影响因子：
8
作者：
Hinderaker, MP;Raines, RT
通讯作者：
Raines, RT