In bacteria, toxin-antitoxin systems can facilitate adaptation to stress and the establishment of persistence and virulence. Researchers at the Institut de Pharmacologie et Biologie Structurale and the Laboratoire de Microbiologie et Génétique Moléculaires in Toulouse have determined the structural bases governing the phenomenon of addiction of toxin-antitoxin systems to a molecular chaperone in the human pathogen Mycobacterium tuberculosis. This work was published in Nature Communications on February 15th, 2019
Toxin-antitoxin systems are genetic elements that can control bacterial growth in response to certain stresses. They are usually composed of a toxin and an antitoxin that inhibits the deleterious effect of the toxin. Under certain stress conditions, the less stable antitoxin is degraded and the toxin released can control bacterial growth by targeting, for example, replication or de novo synthesis of proteins. The involvement of some of these systems in bacterial persistence and in the virulence of certain pathogens makes them pertinent therapeutic targets.
Mycobacterium tuberculosis, the bacterium responsible for tuberculosis, causes close to two millions deaths worldwide each year and still remains a major public health problem. M. tuberculosis possesses a very high number of toxin-antitoxin systems (more than 80) with unknown functions and it has been proposed that these systems could be involved in establishing the persistence phase in this bacterium.
Among these toxin-antitoxin systems, the TAC (Toxin-Antitoxin-Chaperone) system is atypical in that it is controlled by a third obligatory partner: a molecular chaperone that assists folding and prevents the degradation of the antitoxin. Remarkably, the dependence of this toxin-antitoxin system on the chaperone is determined by a small region of the antitoxin, called ChAD (for chaperone addiction), which specifically interacts with the chaperone and induces aggregation of the antitoxin in the absence of the latter.
Using TAC of M. tuberculosis as model system, the researchers solved the crystallographic structure of the chaperone in complex with the ChAD sequence of the antitoxin, thus revealing the molecular bases of the phenomenon of addiction of toxin systems to a chaperone. In addition, this structure and the extensive biochemical and biophysical characterization of the complex have shown that the interaction between the chaperone and antitoxin can be destabilized in vitro and in vivo, inducing controlled activation of the toxin.
Figure: Structure of the complex formed between the chaperone and the ChAD sequence of the M. tuberculosis TAC system. The molecular chaperone is made up of four identical subunits schematized as ribbons of different colours. Two ChAD peptides and the corresponding experimental electron density map (blue mesh) are also shown. © Lionel Mourey
Guillet V, Bordes P, Bon C, Marcoux J, Gervais V, Sala AJ, Dos Reis S, Slama N, Mares-Mejía I, Cirinesi AM, Maveyraud L, Genevaux P*, Mourey L*. Structural insights into chaperone addiction of toxin-antitoxin systems. Nat Commun. 2019 Feb 15;10(1):782. doi: 10.1038/s41467-019-08747-4.
Researcher: Lionel Mourey, Pierre Genevaux
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