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

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 co...

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Autores principales: Vandervelde, Alexandra, Drobnak, Igor, Hadži, San, Sterckx, Yann G.-J., Welte, Thomas, De Greve, Henri, Charlier, Daniel, Efremov, Rouslan, Loris, Remy, Lah, Jurij
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5389731/
https://www.ncbi.nlm.nih.gov/pubmed/28334797
http://dx.doi.org/10.1093/nar/gkx108
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author Vandervelde, Alexandra
Drobnak, Igor
Hadži, San
Sterckx, Yann G.-J.
Welte, Thomas
De Greve, Henri
Charlier, Daniel
Efremov, Rouslan
Loris, Remy
Lah, Jurij
author_facet Vandervelde, Alexandra
Drobnak, Igor
Hadži, San
Sterckx, Yann G.-J.
Welte, Thomas
De Greve, Henri
Charlier, Daniel
Efremov, Rouslan
Loris, Remy
Lah, Jurij
author_sort Vandervelde, Alexandra
collection PubMed
description 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 CcdA(2) for individual binding sites on the operator are enhanced by the toxin CcdB(2), which bridges the CcdA(2) 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.
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spelling pubmed-53897312017-04-24 Molecular mechanism governing ratio-dependent transcription regulation in the ccdAB operon Vandervelde, Alexandra Drobnak, Igor Hadži, San Sterckx, Yann G.-J. Welte, Thomas De Greve, Henri Charlier, Daniel Efremov, Rouslan Loris, Remy Lah, Jurij Nucleic Acids Res NAR Breakthrough Article 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 CcdA(2) for individual binding sites on the operator are enhanced by the toxin CcdB(2), which bridges the CcdA(2) 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. Oxford University Press 2017-04-07 2017-02-17 /pmc/articles/PMC5389731/ /pubmed/28334797 http://dx.doi.org/10.1093/nar/gkx108 Text en © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle NAR Breakthrough Article
Vandervelde, Alexandra
Drobnak, Igor
Hadži, San
Sterckx, Yann G.-J.
Welte, Thomas
De Greve, Henri
Charlier, Daniel
Efremov, Rouslan
Loris, Remy
Lah, Jurij
Molecular mechanism governing ratio-dependent transcription regulation in the ccdAB operon
title Molecular mechanism governing ratio-dependent transcription regulation in the ccdAB operon
title_full Molecular mechanism governing ratio-dependent transcription regulation in the ccdAB operon
title_fullStr Molecular mechanism governing ratio-dependent transcription regulation in the ccdAB operon
title_full_unstemmed Molecular mechanism governing ratio-dependent transcription regulation in the ccdAB operon
title_short Molecular mechanism governing ratio-dependent transcription regulation in the ccdAB operon
title_sort molecular mechanism governing ratio-dependent transcription regulation in the ccdab operon
topic NAR Breakthrough Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5389731/
https://www.ncbi.nlm.nih.gov/pubmed/28334797
http://dx.doi.org/10.1093/nar/gkx108
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