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FEBS Open Bio. 2019 Oct 23. doi: 10.1002/2211-5463.12749. [Epub ahead of print]

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

Author information

1
Inflammation Biology and Cell Signalling Laboratory, National Institute of Pathology, New Delhi, 110029, India.
2
Department of Biophysics, All India Institute of Medical Sciences, New Delhi, 110029, India.
3
JH Institute of Molecular Medicine, Jamia Hamdard, Hamdard Nagar, New Delhi, 110062, India.
4
Department of Biotechnology, Jamia Hamdard, Hamdard Nagar, New Delhi, 110062, India.
5
Medical Research Council, Laboratory of Molecular Biology, Cambridge, CB2 0QH, UK.
6
Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Prof CR Rao Road, Hyderabad, 500007, India.

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 were analysed through Fourier transformed infrared spectroscopy (FTIR). 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 defence 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

PMID:
31643141
DOI:
10.1002/2211-5463.12749
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