Identifying Cognate Binding Pairs among a Large Set of Paralogs: The Case of PE/PPE Proteins of Mycobacterium tuberculosis

We consider the problem of how to detect cognate pairs of proteins that bind when each belongs to a large family of paralogs. To illustrate the problem, we have undertaken a genomewide analysis of interactions of members of the PE and PPE protein families of Mycobacterium tuberculosis. Our computational method uses structural information, operon organization, and protein coevolution to infer the interaction of PE and PPE proteins. Some 289 PE/PPE complexes were predicted out of a possible 5,590 PE/PPE pairs genomewide. Thirty-five of these predicted complexes were also found to have correlated mRNA expression, providing additional evidence for these interactions. We show that our method is applicable to other protein families, by analyzing interactions of the Esx family of proteins. Our resulting set of predictions is a starting point for genomewide experimental interaction screens of the PE and PPE families, and our method may be generally useful for detecting interactions of proteins within families having many paralogs.

本研究旨在解决如何检测结合状态下的同源蛋白质配对（cognate pairs of proteins）的问题，其中每一类蛋白质均隶属于一个庞大的旁系同源蛋白（paralogs）家族。为阐明该研究问题，我们针对结核分枝杆菌（Mycobacterium tuberculosis）PE与PPE蛋白家族成员的相互作用开展了全基因组范围的分析。本研究提出的计算方法借助结构信息、操纵子（operon）组织特征以及蛋白质共进化（coevolution）信息，推断PE与PPE蛋白之间的相互作用。全基因组范围内共存在5590组潜在PE/PPE蛋白配对，我们从中预测得到约289组PE/PPE复合物。其中35组预测复合物被证实存在相关的mRNA表达模式，为这些相互作用提供了额外的实验佐证。通过分析Esx蛋白家族的相互作用，我们证实该方法可推广应用至其他蛋白家族。本研究得到的预测结果集可作为PE与PPE家族全基因组实验相互作用筛选的起始基础，而我们提出的方法对于检测存在大量旁系同源物的家族内部蛋白质相互作用具有普适性应用价值。