Molecular mechanism governing ratio-dependent transcription regulation in the ccdAB operon.

TitleMolecular mechanism governing ratio-dependent transcription regulation in the ccdAB operon.
Publication TypeJournal Article
Year of Publication2017
AuthorsVandervelde, A., I. Drobnak, S. Hadži, Y. G. - J. Sterckx, T. Welte, H. De Greve, D. Charlier, R. G. Efremov, R. Loris, and J. Lah
JournalNucleic Acids Res
Volume45
Issue6
Pagination2937-2950
Date Published2017 Apr 07
ISSN1362-4962
KeywordsBacterial Proteins, Bacterial Toxins, Binding Sites, DNA, Bacterial, Gene Expression Regulation, Bacterial, Models, Molecular, Operator Regions, Genetic, Operon, Protein Binding, Protein Domains, Protein Multimerization, Repressor Proteins, Transcription, Genetic
Abstract

Bacteria can become transiently tolerant to several classes of antibiotics. This phenomenon known as persistence is regulated by small genetic elements called toxin-antitoxin modules with intricate yet often poorly understood self-regulatory features. Here, we describe the structures of molecular complexes and interactions that drive the transcription regulation of the ccdAB toxin-antitoxin module. Low specificity and affinity of the antitoxin CcdA2 for individual binding sites on the operator are enhanced by the toxin CcdB2, which bridges the CcdA2 dimers. This results in a unique extended repressing complex that spirals around the operator and presents equally spaced DNA binding sites. The multivalency of binding sites induces a digital on-off switch for transcription, regulated by the toxin:antitoxin ratio. The ratio at which this switch occurs is modulated by non-specific interactions with the excess chromosomal DNA. Altogether, we present the molecular mechanisms underlying the ratio-dependent transcriptional regulation of the ccdAB operon.

DOI10.1093/nar/gkx108
Alternate JournalNucleic Acids Res.
PubMed ID28334797
PubMed Central IDPMC5389731
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