Mapping allostery through the covariance analysis of NMR chemical shifts
Mapping allostery through the covariance analysis of NMR chemical shifts
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DOI：
10.1073/pnas.1017311108
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发表时间：
2011-04-12
影响因子：
11.1
通讯作者：
Melacini, Giuseppe
中科院分区：
文献类型：
--
作者：
Selvaratnam, Rajeevan;Chowdhury, Somenath;Melacini, Giuseppe
变构作用是生物学中一种基本的调节机制。长程变构扰动终点的残基通常通过比较分析载脂蛋白和效应物结合态的结构和动力学来确定。然而，介导终点之间变构信号传播的相互作用网络通常仍然难以捉摸。在这里，我们表明，由一组共价修饰的变构效应物类似物（即，激动剂和拮抗剂）揭示了偶联残基的延伸网络。出乎意料的是，这样的网络不仅到达受效应器依赖性结构变化的位点，而且还到达受动态驱动的变构控制的区域。在这些区域中，变构信号主要通过动态而不是结构调制来传播，这导致微妙但高度相关的化学位移变化。建议的化学位移协方差分析（CHESCA）确定基于凝聚聚类（AC）和奇异值分解（SVD）的组合残基间的相关性。AC的结果在树状图，定义功能集群的耦合残基，而SVD生成的得分图，提供了一个残基特异性解剖的结合和变构的贡献。CHESCA方法通过将其应用于由cAMP直接激活的交换蛋白（EPAC）的cAMP结合结构域进行验证，并且CHESCA结果与EPAC激活的独立突变数据完全一致。总体而言，CHESCA是一种普遍适用的方法，其利用效应类似物的选定化学文库来定量解码嵌入化学位移变化中的结合和变构信息内容。
Allostery is a fundamental mechanism of regulation in biology. The residues at the end points of long-range allosteric perturbations are commonly identified by the comparative analyses of structures and dynamics in apo and effector-bound states. However, the networks of interactions mediating the propagation of allosteric signals between the end points often remain elusive. Here we show that the covariance analysis of NMR chemical shift changes caused by a set of covalently modified analogs of the allosteric effector (i.e., agonists and antagonists) reveals extended networks of coupled residues. Unexpectedly, such networks reach not only sites subject to effector-dependent structural variations, but also regions that are controlled by dynamically driven allostery. In these regions the allosteric signal is propagated mainly by dynamic rather than structural modulations, which result in subtle but highly correlated chemical shift variations. The proposed chemical shift covariance analysis (CHESCA) identifies interresidue correlations based on the combination of agglomerative clustering (AC) and singular value decomposition (SVD). AC results in dendrograms that define functional clusters of coupled residues, while SVD generates score plots that provide a residue-specific dissection of the contributions to binding and allostery. The CHESCA approach was validated by applying it to the cAMP-binding domain of the exchange protein directly activated by cAMP (EPAC) and the CHESCA results are in full agreement with independent mutational data on EPAC activation. Overall, CHESCA is a generally applicable method that utilizes a selected chemical library of effector analogs to quantitatively decode the binding and allosteric information content embedded in chemical shift changes.