Liu Ying, Bahar Ivet
Department of Computational Biology, School of Medicine, University of Pittsburgh, 3064 BST3, 3501 Fifth Avenue, Pittsburgh, PA 15213, USA.
Pac Symp Biocomput. 2010:269-80. doi: 10.1142/9789814295291_0029.
The ATPase cycle of the heat shock protein 70 (HSP70) is largely dependent on the ability of its nucleotide binding domain (NBD), also called ATPase domain, to undergo structural changes between its open and closed conformations. We present here a combined study of the Hsp70 NBD sequence, structure and dynamic features to identify the residues that play a crucial role in mediating the allosteric signaling properties of the ATPase domain. Specifically, we identify the residues involved in the shortest-path communications of the domain modeled as a network of nodes (residues) and links (equilibrium interactions). By comparing the calculations on both closed and open conformation of Hsp70 NBD, we identified a subset of central residues located at the interface between the two lobes of the NBD near the nucleotide binding site, which form a putative communication pathway invariant to structural changes. Two pairs of residues forming contacts at the interface in the closed conformation of the NBD are observed to no longer interact in the open conformation, suggesting that these specific interactions may play a switch role in establishing the transition of the NBD between the two functional forms. Sequence co-evolution analysis and collective dynamics analysis with elastic network model further confirm the key roles of these residues in Hsp70 NBD dynamics and functions.
热休克蛋白70（HSP70）的ATP酶循环在很大程度上取决于其核苷酸结合结构域（NBD），也称为ATP酶结构域，在开放和闭合构象之间发生结构变化的能力。我们在此展示了一项关于Hsp70 NBD序列、结构和动态特征的综合研究，以确定在介导ATP酶结构域的变构信号特性中起关键作用的残基。具体而言，我们确定了参与该结构域最短路径通信的残基，该结构域被建模为一个节点（残基）和链接（平衡相互作用）的网络。通过比较Hsp70 NBD闭合和开放构象的计算结果，我们确定了位于NBD两个叶之间靠近核苷酸结合位点的界面处的一组中心残基，它们形成了一条对结构变化不变的假定通信途径。观察到在NBD闭合构象中在界面处形成接触的两对残基在开放构象中不再相互作用，这表明这些特定相互作用可能在建立NBD在两种功能形式之间的转变中起开关作用。序列共进化分析和弹性网络模型的集体动力学分析进一步证实了这些残基在Hsp70 NBD动力学和功能中的关键作用。
