Electrostatically accelerated encounter and folding for facile recognition of intrinsically disordered proteins.
Electrostatically accelerated encounter and folding for facile recognition of intrinsically disordered proteins.
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DOI：
10.1371/journal.pcbi.1003363
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发表时间：
2013
影响因子：
4.3
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Ganguly D;Zhang W;Chen J
实现简单的特异性识别对于参与细胞信号传导和调节的内在无序蛋白（IDP）是必不可少的。考虑到蛋白质折叠和扩散限制蛋白质-蛋白质相遇的物理时间尺度，表明蛋白质折叠对特定IDP识别的频繁需求可能导致动力学瓶颈。国内流离失所者如何克服这种潜在的动力学瓶颈，在信号和调节中发挥作用，目前还知之甚少。我们最近对细胞周期调节剂p27的计算和实验研究（Ganguly等人，J. Mol.（2012））证明，施加在IDP的富集电荷上的长程静电力可以通过“静电转向”加速蛋白质-蛋白质相遇，同时促进“折叠能力”相遇拓扑结构以增强相遇时IDP折叠的效率。在这里，我们进一步研究了耦合的结合和折叠机制和静电力的作用，形成三个IDP复合物具有更复杂的折叠拓扑结构。这些复合物的表面静电势缺乏像p27/Cdk 2/细胞周期蛋白A复合物所观察到的那些突出的特征，以直接表明静电力在遇到时促进折叠的能力。尽管如此，类似的静电加速遇到和折叠机制一致预测所有三个复杂的拓扑结构为基础的粗粒度模拟。结合我们以前对已知IDP复合物中电荷分布的分析，我们的研究结果支持静电相互作用在促进有效的耦合结合和折叠以便于特异性识别中的普遍作用。这些结果还表明，可能存在IDP折叠拓扑结构、电荷特性以及耦合的结合和折叠机制的共同进化，至少部分地由实现用于细胞信号传导和调节的快速缔合动力学的需要驱动。内源性无序蛋白（IDP）是调控网络的关键组成部分，决定了细胞决策的各个方面。它们在主要疾病途径中的比例过高，被认为是新的，尽管目前很难药物靶点。IDPs的识别扩展了传统的蛋白质结构-功能范式，并且已经提出了关于内在障碍如何赋予关键功能优势的各种概念。然而，这些概念的物理基础仍然很不牢固。特别是，虽然国内流离失所者单独存在的波动结构的集合体，他们经常折叠后，具体的结合。蛋白质折叠和蛋白质-蛋白质相遇的物理时间尺度的分析预测，肽折叠特异性结合的要求可能导致主要的动力学瓶颈。在这项工作中，仔细校准的基于拓扑结构的粗粒度模型被应用于直接模拟可逆的折叠和结合，并研究识别三个IDP复合物的机制。结果强烈支持静电加速相遇和折叠机制，其中长程静电力不仅通过“静电转向”加速蛋白质-蛋白质相遇，而且还促进“折叠能力”相遇拓扑结构，以提高相遇时IDP折叠的效率。
Achieving facile specific recognition is essential for intrinsically disordered proteins (IDPs) that are involved in cellular signaling and regulation. Consideration of the physical time scales of protein folding and diffusion-limited protein-protein encounter has suggested that the frequent requirement of protein folding for specific IDP recognition could lead to kinetic bottlenecks. How IDPs overcome such potential kinetic bottlenecks to viably function in signaling and regulation in general is poorly understood. Our recent computational and experimental study of cell-cycle regulator p27 (Ganguly et al., J. Mol. Biol. (2012)) demonstrated that long-range electrostatic forces exerted on enriched charges of IDPs could accelerate protein-protein encounter via “electrostatic steering” and at the same time promote “folding-competent” encounter topologies to enhance the efficiency of IDP folding upon encounter. Here, we further investigated the coupled binding and folding mechanisms and the roles of electrostatic forces in the formation of three IDP complexes with more complex folded topologies. The surface electrostatic potentials of these complexes lack prominent features like those observed for the p27/Cdk2/cyclin A complex to directly suggest the ability of electrostatic forces to facilitate folding upon encounter. Nonetheless, similar electrostatically accelerated encounter and folding mechanisms were consistently predicted for all three complexes using topology-based coarse-grained simulations. Together with our previous analysis of charge distributions in known IDP complexes, our results support a prevalent role of electrostatic interactions in promoting efficient coupled binding and folding for facile specific recognition. These results also suggest that there is likely a co-evolution of IDP folded topology, charge characteristics, and coupled binding and folding mechanisms, driven at least partially by the need to achieve fast association kinetics for cellular signaling and regulation. Intrinsically disordered proteins (IDPs) are key components of regulatory networks that dictate various aspects of cellular decision-making. They are over-represented in major disease pathways, and are considered novel albeit currently difficult drug targets. Recognition of IDPs has extended the traditional protein structure-function paradigm, and various concepts have been proposed on how intrinsic disorder may confer crucial functional advantages. However, the physical basis of these concepts remains poorly established. In particular, while IDPs alone exist as ensembles of fluctuating structures, they frequently fold upon specific binding. Analysis of the physical timescales of protein folding and protein-protein encounter predicts that the requirement of peptide folding for specific binding could lead to a major kinetic bottleneck. In this work, carefully calibrated topology-based coarse-grained models were applied to directly simulate reversible folding and binding and investigate the recognition mechanisms of three IDP complexes. The results strongly support an electrostatically accelerated encounter and folding mechanism, where long-range electrostatic forces not only accelerate protein-protein encounter via “electrostatic steering” but also promote “folding-competent” encounter topologies to enhance the efficiency of IDP folding upon encounter.
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影响因子：
64.8
作者：
Demarest, SJ;Martinez-Yamout, M;Wright, PE
通讯作者：
Wright, PE
影响因子：
5.6
作者：
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影响因子：
15
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
4.8
作者：
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通讯作者：
Jemth, Per