Uncovering new pathogenhost proteinprotein interactions by pairwise structure similarity

Abstract

Pathogens usually evade and manipulate host-immune pathways through pathogenhost proteinprotein interactions (PPIs) to avoid being killed by the host immune system. Therefore, uncovering pathogenhost 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 pathogenhost PPIs. First, a high-quality and non-redundant structurestructure 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 residueresidue 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 pathogenhost PPIs of human immunodeficiency virus type 1 (HIV-1) with performance close to that of in vitro highthroughput screening approaches. Finally, a pathogenhost 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 pathogenhost PPIs in the future.