Intrinsic Disordered Controls Transcription of Bacterial Toxin-Antitoixn Modules

Abstract

Intrinsic disorder is highly prevalent in type II bacterial antitoxins. It has long being assumed their presence is linked to the rapid turnover of these antitoxins, however recent evidence suggest they provide unparalleled features that allow moonlighting between toxin neutralization and allosteric control of transcription. Conditional cooperativity the a common mechanism at play for transcription regulation of type II toxin-antitoxin operons and is intricately related to persistence. Conditional cooperativity allows the toxin component of toxin-antitoxin modules to act as a co-repressor at low toxin dose respect to the antitoxin or de-repressor when the toxin level exceeds a certain threshold. It has been suggested that the presence of a disordered region in toxin-antitoxin system may play a central role in their transcription regulation.To address how the antitoxin IDR is involved in transcription regulation we studied the phd/doc operon as model transcription regulation system. We provide evidence that the intrinsically disordered region of Phd is a bona fide entropic barrier that precludes full operon repression in the absence of Doc. Binding of the Doc toxin to Phd results in a cooperativity switch and consequent strong operon repression, enabling context-specific modulation of the transcription output to the regulatory process.The regulation of transcription of TA modules by conditional cooperativity has strong implications in the formation and frequency of persister cells. Variations of this theme are likely a common mechanism in the auto-regulation of bacterial operons that involve intrinsically disordered regions.