Namiko Mitarai (The Niels Bohr Institute)
Many toxin-antitoxin operons are regulated by the toxin/antitoxin ratio by mechanisms collectively coined ”conditional cooperativity”. Toxin and antitoxin form heteromers with different stoichiometric ratios, and the complex with the intermediate ratio works best as a transcription repressor. This allows transcription at low toxin level, strong repression at intermediate toxinlevel, and then again transcription at high toxin level ( and references therein). Such regulation has two interesting features; firstly, it provides a non-monotonous response to the concentration of one of the proteins, and secondly, it opens for ultra-sensitivity mediated by the sequestration of the functioning heteromers. We explore possible functions of conditional regulation in simple feedback motifs, and show that it can provide bistability for wide a range of parameters . We demonstrate that the conditional cooperativity in toxin-antitoxin systems combined with the growth-inhibition activity of free toxin can mediate bistability between a growing state and a dormant state. Conditional cooperativity also secures that the antitoxin dominated state has a substantial amount of toxins present, which helps the transition to the toxin dominated state under stress. These features may be relevant for understanding persister formation in E. coli.  I. Cataudella, A.Trusina, K. Sneppen, K. Gerdes, and N. Mitarai, Nucl. Acids Res. (2012) 40, 6424-6434.  I. Cataudella, K. Sneppen, K. Gerdes, and N. Mitarai, Plos. Comput. Biol. (2013) 8, e1003174.