Stetz Gabrielle, Verkhivker Gennady M
Graduate Program in Computational and Data Sciences, Schmid College of Science and Technology, Chapman University, Orange, California, United States of America.
Chapman University School of Pharmacy, Irvine, California, United States of America.
PLoS Comput Biol. 2017 Jan 17;13(1):e1005299. doi: 10.1371/journal.pcbi.1005299. eCollection 2017 Jan.
Allosteric interactions in the Hsp70 proteins are linked with their regulatory mechanisms and cellular functions. Despite significant progress in structural and functional characterization of the Hsp70 proteins fundamental questions concerning modularity of the allosteric interaction networks and hierarchy of signaling pathways in the Hsp70 chaperones remained largely unexplored and poorly understood. In this work, we proposed an integrated computational strategy that combined atomistic and coarse-grained simulations with coevolutionary analysis and network modeling of the residue interactions. A novel aspect of this work is the incorporation of dynamic residue correlations and coevolutionary residue dependencies in the construction of allosteric interaction networks and signaling pathways. We found that functional sites involved in allosteric regulation of Hsp70 may be characterized by structural stability, proximity to global hinge centers and local structural environment that is enriched by highly coevolving flexible residues. These specific characteristics may be necessary for regulation of allosteric structural transitions and could distinguish regulatory sites from nonfunctional conserved residues. The observed confluence of dynamics correlations and coevolutionary residue couplings with global networking features may determine modular organization of allosteric interactions and dictate localization of key mediating sites. Community analysis of the residue interaction networks revealed that concerted rearrangements of local interacting modules at the inter-domain interface may be responsible for global structural changes and a population shift in the DnaK chaperone. The inter-domain communities in the Hsp70 structures harbor the majority of regulatory residues involved in allosteric signaling, suggesting that these sites could be integral to the network organization and coordination of structural changes. Using a network-based formalism of allostery, we introduced a community-hopping model of allosteric communication. Atomistic reconstruction of signaling pathways in the DnaK structures captured a direction-specific mechanism and molecular details of signal transmission that are fully consistent with the mutagenesis experiments. The results of our study reconciled structural and functional experiments from a network-centric perspective by showing that global properties of the residue interaction networks and coevolutionary signatures may be linked with specificity and diversity of allosteric regulation mechanisms.
热休克蛋白70（Hsp70）家族蛋白质中的变构相互作用与其调节机制和细胞功能相关联。尽管在Hsp70蛋白质的结构和功能表征方面取得了显著进展，但关于Hsp70伴侣蛋白变构相互作用网络的模块化以及信号通路层次结构的基本问题在很大程度上仍未得到探索，且了解甚少。在这项工作中，我们提出了一种综合计算策略，该策略将原子尺度和粗粒度模拟与共进化分析以及残基相互作用的网络建模相结合。这项工作的一个新颖之处在于，在构建变构相互作用网络和信号通路时纳入了动态残基相关性和共进化残基依赖性。我们发现，参与Hsp70变构调节的功能位点可能具有结构稳定性、靠近全局铰链中心以及由高度共进化的柔性残基丰富的局部结构环境等特征。这些特定特征对于变构结构转变的调节可能是必要的，并且可以将调节位点与无功能的保守残基区分开来。观察到的动力学相关性和共进化残基耦合与全局网络特征的融合可能决定变构相互作用的模块化组织，并决定关键介导位点的定位。对残基相互作用网络的群落分析表明，结构域间界面处局部相互作用模块的协同重排可能是DnaK伴侣蛋白全局结构变化和群体转移的原因。Hsp70结构中的结构域间群落包含了参与变构信号传导的大多数调节残基，这表明这些位点可能是网络组织和结构变化协调所不可或缺的。使用基于网络的变构形式，我们引入了一种变构通信的群落跳跃模型。DnaK结构中信号通路的原子尺度重建捕捉到了一种方向特异性机制以及与诱变实验完全一致的信号传递分子细节。我们的研究结果从以网络为中心的角度协调了结构和功能实验，表明残基相互作用网络的全局特性和共进化特征可能与变构调节机制的特异性和多样性相关联。
