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

Alexandra Vandervelde, Igor Drobnak, San Hadzi, Yann Sterckx, Thomas Welte, Henri De Greve, Daniel Charlier, Rouslan Efremov, Remy Loris, Jurij Lah

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)2937-2950
Number of pages14
JournalNucleic Acids Res
Issue number6
Publication statusPublished - 7 Apr 2017

Bibliographical note

© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.


  • Structural biology
  • Electron microscopy
  • Thermodynamics
  • Biophysics
  • Transcription regulation
  • Toxin-Antitoxin module
  • Bacterial stress response
  • Persistence
  • Operon
  • Protein Multimerization
  • Models, Molecular
  • Bacterial Toxins/chemistry
  • Repressor Proteins/chemistry
  • Protein Binding
  • Protein Domains
  • Transcription, Genetic
  • Bacterial Proteins/chemistry
  • DNA, Bacterial/chemistry
  • Operator Regions, Genetic
  • Gene Expression Regulation, Bacterial
  • Binding Sites


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