Integrating Multimeric Threading With High-throughput Experiments for Structural Interactome of Escherichia coli
Integrating Multimeric Threading With High-throughput Experiments for Structural Interactome of Escherichia coli
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DOI：
10.1016/j.jmb.2021.166944
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发表时间：
2021-03-25
影响因子：
5.6
通讯作者：
Zhang, Yang
中科院分区：
文献类型：
--
作者：
Gong, Weikang;Guerler, Aysam;Zhang, Yang
全基因组蛋白质-蛋白质相互作用（PPI）的测定仍然是结构生物学中尚未解决的重要问题。困难是双重的，因为高通量实验（HTE）在分配PPI时通常具有相对较高的假阳性率，并且PPI四级结构比使用传统结构生物学技术的三级结构更难解决。我们提出了一个统一的管道，Threpp，以解决这两个问题。从一对单体序列开始，Threpp首先将两个序列通过复杂结构文库，其中使用朴素贝叶斯分类器模型将比对得分与HTE数据组合以预测两个链彼此相互作用的可能性。接下来，通过界面特异性结构比对与二聚体螺纹框架重组单体比对，构建所鉴定PPI的四级复合物结构。该管道应用于大肠杆菌基因组，产生了35，125个置信PPI，比单独的HTE高4.5倍。PPI网络的图形分析显示了无标度的簇大小分布，与以前的研究一致，这被发现对基因组进化的鲁棒性和对大肠杆菌至关重要的功能重要蛋白质的中心性至关重要。大肠杆菌存活率。此外，对所有预测的E.其中6771个被发现具有高置信度分数，对应于复合物的正确折叠，TM分数>0.5，并且39个显示出与后来发布的实验结构的紧密一致性，平均TM分数= 0.73。这些结果证明了基于线程的同源建模在全基因组PPI网络检测和复杂结构构建中的显著有用性。(C)2021爱思唯尔有限公司保留所有权利。
Genome-wide protein-protein interaction (PPI) determination remains a significant unsolved problem in structural biology. The difficulty is twofold since high-throughput experiments (HTEs) have often a relatively high false-positive rate in assigning PPIs, and PPI quaternary structures are more difficult to solve than tertiary structures using traditional structural biology techniques. We proposed a uniform pipeline, Threpp, to address both problems. Starting from a pair of monomer sequences, Threpp first threads both sequences through a complex structure library, where the alignment score is combined with HTE data using a naive Bayesian classifier model to predict the likelihood of two chains to interact with each other. Next, quaternary complex structures of the identified PPIs are constructed by reassembling monomeric alignments with dimeric threading frameworks through interface-specific structural alignments. The pipeline was applied to the Escherichia coli genome and created 35,125 confident PPIs which is 4.5-fold higher than HTE alone. Graphic analyses of the PPI networks show a scale-free cluster size distribution, consistent with previous studies, which was found critical to the robustness of genome evolution and the centrality of functionally important proteins that are essential to E. coli survival. Furthermore, complex structure models were constructed for all predicted E. coli PPIs based on the quaternary threading alignments, where 6771 of them were found to have a high confidence score that corresponds to the correct fold of the complexes with a TM-score >0.5, and 39 showed a close consistency with the later released experimental structures with an average TM-score = 0.73. These results demonstrated the significant usefulness of threading-based homologous modeling in both genome-wide PPI network detection and complex structural construction. (C) 2021 Elsevier Ltd. All rights reserved.