Disorder-to-order transition in PE-PPE proteins of Mycobacterium tuberculosis augments the pro-pathogen immune response

FEBS Open Bio. 2020 Jan;10(1):70-85. doi: 10.1002/2211-5463.12749. Epub 2019 Dec 17.

Abstract

A growing body of evidence supports the hypothesis that intrinsically disordered proteins often mediate host-pathogen interactions and modulate host functions for pathogen survival and virulence. Mycobacterium tuberculosis (M.tb) has evolved largely through reductive evolution, with a few exceptions such as the glycine-alanine-rich PE-PPE/PGRS protein family, which has been expanding in pathogenic mycobacteria. Here, our analyses of the M.tb proteome and secretome revealed that the PE-PGRS subfamily is enriched for disordered regions and disordered binding sites, pointing to their importance in host-pathogen interactions. As a case study, the secondary structure of PE35-PPE68 and PE32-PPE65 of the pathogenesis-related RD1 and RD8 regions was analyzed through Fourier-transform infrared spectroscopy. These disordered proteins displayed a considerable structural shift from disordered to ordered while engaged in the formation of complexes. While these proteins are immunogenic individually and enhance the pro-pathogen response, their corresponding complexes enhanced the responses manifold as displayed here by PE35 and PPE68. It is likely that M.tb exploits such disorder-order structural dynamics as a strategy to mount a pro-pathogen response and subvert host defense for productive infection. This functional gain also serves as a means to compensate genomic content loss due to reductive evolution.

Keywords: Mycobacterium tuberculosis; folding-upon-binding; immune modulation; immunogenicity; pathogenesis; protein-protein interaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Proteins / chemistry*
  • Bacterial Proteins / immunology*
  • Bacterial Proteins / isolation & purification
  • Cells, Cultured
  • Computational Biology
  • Glutamic Acid / chemistry*
  • Glutamic Acid / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mycobacterium tuberculosis / immunology*
  • Mycobacterium tuberculosis / pathogenicity
  • Proline / chemistry*
  • Proline / immunology
  • Proteome

Substances

  • Bacterial Proteins
  • Proteome
  • Glutamic Acid
  • Proline