Abstract
Mycobacterium tuberculosis genome encodes over 80 toxin–antitoxin (TA) systems. While each toxin interacts with its cognate antitoxin, the abundance of TA systems presents an opportunity for potential non-cognate interactions. TA systems mediate manifold interactions to manage pathogenicity and stress response network of the cell and non-cognate interactions may play vital roles as well. To address if non-cognate and heterologous interactions are feasible and to understand the structural basis of their interactions, we have performed comprehensive computational analyses on the available 3D structures and generated structural models of paralogous M. tuberculosis VapBC and MazEF TA systems. For a majority of the TA systems, we show that non-cognate toxin–antitoxin interactions are structurally incompatible except for complexes like VapBC15 and VapBC11, which show similar interfaces and potential for cross-reactivity. For TA systems which have been experimentally shown earlier to disfavor non-cognate interactions, we demonstrate that they are structurally and stereo-chemically incompatible. For selected TA systems, our detailed structural analysis identifies specificity conferring residues. Thus, our work improves the current understanding of TA interfaces and generates a hypothesis based on congenial binding site, geometric complementarity, and chemical nature of interfaces. Overall, our work offers a structure-based explanation for non-cognate toxin-antitoxin interactions in M. tuberculosis.
Highlights
For a long time, the general function of toxin–antitoxin (TA) systems, was believed to be only that of plasmid addiction
Our work offers a structure-based explanation for non-cognate toxin-antitoxin interactions in M. tuberculosis
VapC toxin sequences in M. tuberculosis, we had earlier proposed that they may be grouped into sub-clusters suggesting close relationships among few TA systems [20]
Summary
The general function of toxin–antitoxin (TA) systems, was believed to be only that of plasmid addiction. While many studies have reported their role in persistence and cell death [5,6,7], it is not clear to what extent these interactions are coupled in the context of their cellular function. Toxins 2020, 12, 481 systems in Mycobacterium tuberculosis raises the possibility of a complex network of interactions among. An intriguing and exciting possibility is cross-talk (or cross- interactions) among non-cognate toxins and antitoxins. By cross-talk, we mean that if toxins X1 and X2 and their respective cognate antitoxins Y1 and Y2 are expressed in the cell at the same time and share similar features, in principle, Y1 can neutralize X2 or Y2 can neutralize X1. While the cognate interactions between X1 and X2 and Y1 and Y2 are expected, non-cognate or cross interaction between
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