Abstract
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.
Highlights
Tuberculosis remains a health problem of global importance [1]
Assumptions We assumed that each interacting pair of PE/PPE proteins must have complementary interfaces, and that the residues in these interfaces may coevolve due to positive selective pressure on the interaction
The components of protein complexes and metabolic pathways in prokaryotes are often located together on the genome in operons [19]. These operons are transcribed as a single, polycistronic mRNA
Summary
Despite the availability of the genome sequence of Mycobacterium tuberculosis (Mtb) for nearly a decade [2], the biology of the pathogen, the molecular mechanisms by which it achieves virulence, remains poorly understood. The PE and PPE Families The PE and PPE gene families in Mtb make up nearly 10% of the bacterium’s coding DNA [2]. PPE proteins have been found on the cell surface [8,9], may be secreted [10], and can confer virulence [11]. These studies indicate the likely importance of the PE and PPE gene families in pathogenesis. More extensive characterization of their function, interactions, and roles in infection are important areas for investigation
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