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Structural basis of thiol-based regulation of formaldehyde detoxification in H. influenzae by a MerR regulator with no sensor region
Pathogenic bacteria such as Haemophilus influenzae, a major cause of lower respiratory tract diseases, must cope with a range of electrophiles generated in the host or by endogenous metabolism. Formaldehyde is one such compound that can irreversibly damage proteins and DNA through alkylation and cro...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5001606/ https://www.ncbi.nlm.nih.gov/pubmed/27307602 http://dx.doi.org/10.1093/nar/gkw543 |
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author | Couñago, Rafael M. Chen, Nathan H. Chang, Chiung-Wen Djoko, Karrera Y. McEwan, Alastair G. Kobe, Bostjan |
author_facet | Couñago, Rafael M. Chen, Nathan H. Chang, Chiung-Wen Djoko, Karrera Y. McEwan, Alastair G. Kobe, Bostjan |
author_sort | Couñago, Rafael M. |
collection | PubMed |
description | Pathogenic bacteria such as Haemophilus influenzae, a major cause of lower respiratory tract diseases, must cope with a range of electrophiles generated in the host or by endogenous metabolism. Formaldehyde is one such compound that can irreversibly damage proteins and DNA through alkylation and cross-linking and interfere with redox homeostasis. Its detoxification operates under the control of HiNmlR, a protein from the MerR family that lacks a specific sensor region and does not bind metal ions. We demonstrate that HiNmlR is a thiol-dependent transcription factor that modulates H. influenzae response to formaldehyde, with two cysteine residues (Cys54 and Cys71) identified to be important for its response against a formaldehyde challenge. We obtained crystal structures of HiNmlR in both the DNA-free and two DNA-bound forms, which suggest that HiNmlR enhances target gene transcription by twisting of operator DNA sequences in a two-gene operon containing overlapping promoters. Our work provides the first structural insights into the mechanism of action of MerR regulators that lack sensor regions. |
format | Online Article Text |
id | pubmed-5001606 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-50016062016-12-07 Structural basis of thiol-based regulation of formaldehyde detoxification in H. influenzae by a MerR regulator with no sensor region Couñago, Rafael M. Chen, Nathan H. Chang, Chiung-Wen Djoko, Karrera Y. McEwan, Alastair G. Kobe, Bostjan Nucleic Acids Res Structural Biology Pathogenic bacteria such as Haemophilus influenzae, a major cause of lower respiratory tract diseases, must cope with a range of electrophiles generated in the host or by endogenous metabolism. Formaldehyde is one such compound that can irreversibly damage proteins and DNA through alkylation and cross-linking and interfere with redox homeostasis. Its detoxification operates under the control of HiNmlR, a protein from the MerR family that lacks a specific sensor region and does not bind metal ions. We demonstrate that HiNmlR is a thiol-dependent transcription factor that modulates H. influenzae response to formaldehyde, with two cysteine residues (Cys54 and Cys71) identified to be important for its response against a formaldehyde challenge. We obtained crystal structures of HiNmlR in both the DNA-free and two DNA-bound forms, which suggest that HiNmlR enhances target gene transcription by twisting of operator DNA sequences in a two-gene operon containing overlapping promoters. Our work provides the first structural insights into the mechanism of action of MerR regulators that lack sensor regions. Oxford University Press 2016-08-19 2016-06-15 /pmc/articles/PMC5001606/ /pubmed/27307602 http://dx.doi.org/10.1093/nar/gkw543 Text en © The Author(s) 2016. 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 | Structural Biology Couñago, Rafael M. Chen, Nathan H. Chang, Chiung-Wen Djoko, Karrera Y. McEwan, Alastair G. Kobe, Bostjan Structural basis of thiol-based regulation of formaldehyde detoxification in H. influenzae by a MerR regulator with no sensor region |
title | Structural basis of thiol-based regulation of formaldehyde detoxification in H. influenzae by a MerR regulator with no sensor region |
title_full | Structural basis of thiol-based regulation of formaldehyde detoxification in H. influenzae by a MerR regulator with no sensor region |
title_fullStr | Structural basis of thiol-based regulation of formaldehyde detoxification in H. influenzae by a MerR regulator with no sensor region |
title_full_unstemmed | Structural basis of thiol-based regulation of formaldehyde detoxification in H. influenzae by a MerR regulator with no sensor region |
title_short | Structural basis of thiol-based regulation of formaldehyde detoxification in H. influenzae by a MerR regulator with no sensor region |
title_sort | structural basis of thiol-based regulation of formaldehyde detoxification in h. influenzae by a merr regulator with no sensor region |
topic | Structural Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5001606/ https://www.ncbi.nlm.nih.gov/pubmed/27307602 http://dx.doi.org/10.1093/nar/gkw543 |
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