Integrating Multifaceted Information to Predict Mycobacterium tuberculosis-Human Protein-Protein Interactions

J Proteome Res. 2018 Nov 2;17(11):3810-3823. doi: 10.1021/acs.jproteome.8b00497. Epub 2018 Oct 16.

Abstract

Tuberculosis (TB) is one of the biggest infectious disease killers caused by Mycobacterium tuberculosis (MTB). Studying the protein-protein interactions (PPIs) between MTB and human can deepen our understanding of the pathogenesis of TB and offer new clues to the treatment against MTB infection, but the experimentally validated interactions are especially scarce in this regard. Herein we proposed an integrated framework that combined template-, domain-domain interaction-, and machine learning-based methods to predict MTB-human PPIs. As a result, we established a network composed of 13 758 PPIs including 451 MTB proteins and 3167 human proteins ( http://liulab.hzau.edu.cn/MTB/ ). Compared to known human targets of various pathogens, our predicted human targets show a similar tendency in terms of the network topological properties and enrichment in important functional genes. Additionally, these human targets largely have longer sequence lengths, more protein domains, more disordered residues, lower evolutionary rates, and older protein ages. Functional analysis demonstrates that these proteins show strong preferences toward the phosphorylation, kinase activity, and signaling transduction processes and the disease and immune related pathways. Dissecting the cross-talk among top-ranked pathways suggests that the cancer pathway may serve as a bridge in MTB infection. Triplet analysis illustrates that the paired targets interacting with the same partner are adjacent to each other in the intraspecies network and tend to share similar expression patterns. Finally, we identified 36 potential anti-MTB human targets by integrating known drug target information and molecular properties of proteins.

Keywords: drug target; functional analysis; protein-protein interactions; tuberculosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / pharmacology*
  • Bacterial Proteins / antagonists & inhibitors
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Host-Pathogen Interactions / drug effects
  • Humans
  • Machine Learning
  • Molecular Targeted Therapy / methods
  • Mycobacterium tuberculosis / chemistry
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / growth & development
  • Mycobacterium tuberculosis / pathogenicity
  • Phosphorylation
  • Protein Interaction Mapping*
  • Protein Interaction Maps*
  • Protein Processing, Post-Translational*
  • Signal Transduction
  • Tuberculosis, Pulmonary / drug therapy*
  • Tuberculosis, Pulmonary / immunology
  • Tuberculosis, Pulmonary / microbiology
  • Tuberculosis, Pulmonary / pathology

Substances

  • Antitubercular Agents
  • Bacterial Proteins