Intrinsically Disordered Regions/Proteins Compensate For Genomic Economization In Mycobacterium Tuberculosis

Abstract

Central to the emergence of Mycobacterium tuberculosis (M. tb) as an extremely successful pathogen is its predilection to persist within the hostile host environment. In this context, the role of disordered proteins and linear motif rich intrinsically disordered proteins (IDPs) to perturb and hijack host cell networks for a productive infection holds special importance. M.tb has a relatively high percentage of IDPs in its proteome among prokaryotes, the significance of which is not known. Moreover, M.tb has evolved through reductive evolution, with the exception of PE‐PPE/PGRS protein family, which has been expanding in pathogenic mycobacteria. Here, we analyzed the M.tb proteome and its entire secretome. PE‐PGRS subfamily and the secretome were enriched in disorder and disordered binding sites, implying that structural disorder might be important for host‐pathogen interactions. We studied the PPE37 protein in more detail that carries an N‐terminal PPE domain capable of iron binding followed by two transmembrane domains and a disordered C‐terminal segment harboring number of eukaryotic linear motifs (ELMs). N‐terminal segment caused proliferation and differentiation of monocytic THP‐1 cells into CD11c, DC‐SIGN positive semi‐mature dendritic cells. The C‐terminal segment localizes to macrophage nucleus and induced caspase‐3 dependent apoptosis of host cells. We also studied the structural shift in PE35‐PPE68 and PE32‐PPE65 protein pairs of pathogenesis‐related RD1 and RD8 regions by analyzing their secondary structure through Fourier transformed infrared spectroscopy. These disordered proteins displayed a remarkable structural shift from disorder to order while engaging in the formation of complexes. These proteins are immunogenic individually and enhance pro‐pathogen response; however, their corresponding complexes enhanced the responses manifold in immunized mice. These results support the role of IDPs in performing contrasting activities to modulate the host processes possibly through molecular mimicry and cross talk. The results from our study further reinforce structural dynamics as a strategy to subvert host defence and to compensate genomic content loss due to reductional evolution.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.