Contact rearrangements form coupled networks from local motions in allosteric proteins
Contact rearrangements form coupled networks from local motions in allosteric proteins
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DOI：
10.1002/prot.21800
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发表时间：
2008-04-01
影响因子：
2.9
通讯作者：
Gray, Jeffrey J.
中科院分区：
文献类型：
--
作者：
Daily, Michael D.;Upadhyaya, Tarak J.;Gray, Jeffrey J.
变构蛋白在一个部位与效应分子结合，导致第二个部位的功能改变。我们假设，改变的、形成的或断开的接触网络对蛋白质中的变构通讯有重要贡献。在这项工作中，我们识别出两个变构结构的残基-残基接触网络之间的哪些相互作用发生了显著变化，并将这些变化组织成图。我们对15对变构结构进行了分析，其中效应器和底物各存在于两个结构中的至少一个结构中。大多数蛋白质都显示出大而密集的接触重排区域，这些图在其中五种蛋白质的变构效应和底物位置之间形成了连接的路径。在剩下的10个蛋白质中，除了接触重排网络之外，可能还需要大规模的构象变化，如刚体运动，以解释底物-效应器的通信。平均而言，包含至少一个底物或效应器分子的簇占蛋白质的20%。这些变构图是小世界；也就是说，它们通常具有与相应随机图的平均最短路径长度相当的平均最短路径长度，并且相对于随机图的平均聚类系数增强。该网络捕获了三种蛋白质中已知的变构扰动突变的60%-80%，并且度量度和贴近度在统计上是这三种蛋白质中两种蛋白质中突变残基和非突变残基的很好的区分器。对于两种蛋白质，共同进化的残基簇被认为是变构重要的，与接触重排最多的区域不同。调节正常模式波动的残基和接触也经常参与接触重排网络。总之，残基-残基接触重排网络提供了由耦合局部运动引起的变构路径部分的有用表示。
Allosteric proteins bind an effector molecule at one site resulting in a functional change at a second site. We hypothesize that networks of contacts altered, formed, or broken are a significant contributor to allosteric communication in proteins. In this work, we identify which interactions change significantly between the residue-residue contact networks of two allosteric structures and then organize these changes into graphs. We perform the analysis on 15 pairs of allosteric structures with effector and substrate each present in at least one of the two structures. Most proteins exhibit large, dense regions of contact rearrangement, and the graphs form connected paths between allosteric effector and substrate sites in five of these proteins. In the remaining 10 proteins, large-scale conformational changes such as rigid-body motions are likely required in addition to contact rearrangement networks to account for substrate-effector communication. On average, clusters which contain at least one substrate or effector molecule comprise 20% of the protein. These allosteric graphs are small worlds; that is, they typically have mean shortest path lengths comparable to those of corresponding random graphs and average clustering coefficients enhanced relative to those of random graphs. The networks capture 60-80% of known allostery-perturbing mutants in three proteins, and the metrics degree and closeness are statistically good discriminators of mutant residues from nonmutant residues within the networks in two of these three proteins. For two proteins, coevolving clusters of residues which have been hypothesized to be allosterically important differ from the regions with the most contact rearrangement. Residues and contacts which modulate normal mode fluctuations also often participate in the contact rearrangement networks. In summary, residue-residue contact rearrangement networks provide useful representations of the portions of allosteric pathways resulting from coupled local motions.