Binding-induced folding of a natively unstructured transcription factor.
Binding-induced folding of a natively unstructured transcription factor.
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结合诱导的本性非结构化转录因子的折叠。
DOI：
10.1371/journal.pcbi.1000060
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发表时间：
2008-04-11
影响因子：
4.3
通讯作者：
Hummer, Gerhard
中科院分区：
文献类型：
--
作者：
Turjanski, Adrian Gustavo;Gutkind, J. Silvio;Best, Robert B.;Hummer, Gerhard
转录因子是控制基因表达的细胞内调控网络的核心组成部分。在人类转录因子中越来越被认识到的现象是在靶结合时形成结构。在这里，我们研究CREB的pKID结构域的折叠和结合的共激活因子CBP的KIX结构域。我们的基于拓扑的Gō-type模型的模拟预测耦合折叠和绑定机制，以及部分绑定中间体的存在。通过过渡路径和Φ值分析，我们发现绑定过渡状态类似于解决方案中的非结构化状态，这意味着CREB只有在提交绑定后才变得结构化。结合后的结构变化让人想起诱导配合机制，并与其中结合发生在平衡时存在于未结合状态的预结构化构象的模型形成对比。有趣的是，增加未结合的pKID中的结构量会降低结合速率，这表明了一种“飞投”样过程。我们发现，包括有吸引力的非本地相互作用的结果在形成非特异性的遭遇复合物，提高结合率，但不显着改变的结合机制。我们的研究有助于解释非结构化如何在蛋白质靶点识别中赋予优势。模拟结果与最近报道的核磁共振研究结果基本一致，并有助于解释实验结合动力学。蛋白质-蛋白质相互作用是许多生理过程的核心。传统上，从X射线晶体学或NMR光谱学获得的分离蛋白质的原子结构被认为决定了分子识别和结合过程。然而，这一观点受到了天然非结构化蛋白质的发现的挑战，包括许多人类转录因子，它们只有在与其靶结合时才呈现有序的分子结构。理解这些从解离和未折叠状态到结合和折叠状态的转变是解开转录因子如何发挥功能的关键，转录因子是控制遗传信息从DNA转录到RNA的系统中所涉及的蛋白质。我们进行了分子模拟，以研究一个良好的特点转录/共转录因子复合物的结合。我们发现，转录因子是非结构化的结合时，其合作伙伴，折叠成一个有序的结构发生后，最初的结合事件。由此产生的耦合折叠和结合机制被发现是在雅阁与国家的最先进的实验数据。非结构化状态下的转录因子结合可以通过加速缔合速率而赋予蛋白质靶识别的优势，而不损害以高特异性和相对低的亲和力结合不同蛋白质组的能力。
Transcription factors are central components of the intracellular regulatory networks that control gene expression. An increasingly recognized phenomenon among human transcription factors is the formation of structure upon target binding. Here, we study the folding and binding of the pKID domain of CREB to the KIX domain of the co-activator CBP. Our simulations of a topology-based Gō-type model predict a coupled folding and binding mechanism, and the existence of partially bound intermediates. From transition-path and Φ-value analyses, we find that the binding transition state resembles the unstructured state in solution, implying that CREB becomes structured only after committing to binding. A change of structure following binding is reminiscent of an induced-fit mechanism and contrasts with models in which binding occurs to pre-structured conformations that exist in the unbound state at equilibrium. Interestingly, increasing the amount of structure in the unbound pKID reduces the rate of binding, suggesting a “fly-casting”-like process. We find that the inclusion of attractive non-native interactions results in the formation of non-specific encounter complexes that enhance the on-rate of binding, but do not significantly change the binding mechanism. Our study helps explain how being unstructured can confer an advantage in protein target recognition. The simulations are in general agreement with the results of a recently reported nuclear magnetic resonance study, and aid in the interpretation of the experimental binding kinetics. Protein-protein interactions are central to many physiological processes. Traditionally, the atomic structure of the isolated proteins, as obtained from X-ray crystallography or NMR spectroscopy, has been thought to determine the molecular recognition and binding process. However, this view has been challenged by the discovery of natively unstructured proteins, including many human transcription factors, which assume ordered molecular structures only upon binding to their targets. Understanding these transitions from a dissociated and unfolded state to a bound and folded state is key to unraveling how transcription factors, proteins involved in the system that controls the transcription of genetic information from DNA to RNA, perform their function. We conducted molecular simulations to study the binding of a well characterized transcription/co-transcription factor complex. We found that the transcription factor is unstructured when binding to its partner, with folding into an ordered structure occurring only after the initial binding event. The resulting coupled folding-and-binding mechanism is found to be in accord with state-of-the-art experimental data. Transcription-factor binding in an unstructured state may confer an advantage in protein target recognition by accelerating the rate of association without compromising the ability to bind to a diverse set of proteins with high specificity and yet relatively low affinity.
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影响因子：
5.6
作者：
De Guzman, RN;Goto, NK;Wright, PE
通讯作者：
Wright, PE
DOI：
10.1073/pnas.2335541100
发表时间：
2003-11-25
影响因子：
11.1
作者：
García, AE;Onuchic, JN
通讯作者：
Onuchic, JN
DOI：
10.1073/pnas.0408098102
发表时间：
2005-05-10
影响因子：
11.1
作者：
Best, RB;Hummer, G
通讯作者：
Hummer, G
影响因子：
3
作者：
BROOKS, BR;BRUCCOLERI, RE;KARPLUS, M
通讯作者：
KARPLUS, M
影响因子：
8.6
作者：
Best, RB;Hummer, G
通讯作者：
Hummer, G