Uncovering New Pathogen-Host Protein-Protein Interactions by Pairwise Structure Similarity

• Published in: PloS one Vol. 11; no. 1; p. e0147612
• Main Authors: Cui, Tao, Li, Weihui, Liu, Lei, Huang, Qiaoyun, He, Zheng-Guo
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 22.01.2016; Public Library of Science (PLoS)
• Subjects: Autophagy; Bacterial Proteins - genetics; Bacterial Proteins - immunology; Biology and Life Sciences; Computer applications; Construction; Genetic aspects; Genomes; Health aspects; High-throughput screening; HIV; Host-Pathogen Interactions - genetics; Host-Pathogen Interactions - physiology; Human immunodeficiency virus; Humans; Immune response; Immune system; Infections; Kinases; Laboratories; Localization; Medicine and Health Sciences; Methods; Mycobacterium tuberculosis; Mycobacterium tuberculosis - genetics; Mycobacterium tuberculosis - immunology; Ontology; Pathogens; Phagocytosis; Protein interaction; Protein Interaction Domains and Motifs - genetics; Protein Interaction Domains and Motifs - physiology; Protein structure; Protein-protein interactions; Proteins; Proteome - genetics; Research and Analysis Methods; Shigella; Shigella flexneri; Similarity; Structural Homology, Protein; Structure-Activity Relationship; Survival; Tuberculosis; Tuberculosis - immunology; Tuberculosis - microbiology; Viruses; United States; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0147612

Pathogens usually evade and manipulate host-immune pathways through pathogen-host protein-protein interactions (PPIs) to avoid being killed by the host immune system. Therefore, uncovering pathogen-host PPIs is critical for determining the mechanisms underlying pathogen infection and survival. In this study, we developed a computational method, which we named pairwise structure similarity (PSS)-PPI, to predict pathogen-host PPIs. First, a high-quality and non-redundant structure-structure interaction (SSI) template library was constructed by exhaustively exploring heteromeric protein complex structures in the PDB database. New interactions were then predicted by searching for PSS with complex structures in the SSI template library. A quantitative score named the PSS score, which integrated structure similarity and residue-residue contact-coverage information, was used to describe the overall similarity of each predicted interaction with the corresponding SSI template. Notably, PSS-PPI yielded experimentally confirmed pathogen-host PPIs of human immunodeficiency virus type 1 (HIV-1) with performance close to that of in vitro high-throughput screening approaches. Finally, a pathogen-host PPI network of human pathogen Mycobacterium tuberculosis, the causative agent of tuberculosis, was constructed using PSS-PPI and refined using filtration steps based on cellular localization information. Analysis of the resulting network indicated that secreted proteins of the STPK, ESX-1, and PE/PPE family in M. tuberculosis targeted human proteins involved in immune response and phagocytosis. M. tuberculosis also targeted host factors known to regulate HIV replication. Taken together, our findings provide insights into the survival mechanisms of M. tuberculosis in human hosts, as well as co-infection of tuberculosis and HIV. With the rapid pace of three-dimensional protein structure discovery, the SSI template library we constructed and the PSS-PPI method we devised can be used to uncover new pathogen-host PPIs in the future.