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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.

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


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.


Mycobacterium tuberculosis ; Folding-upon-binding; Immune modulation; Immunogenicity; Pathogenesis; Protein-protein interaction

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