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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...

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Autores principales: Couñago, Rafael M., Chen, Nathan H., Chang, Chiung-Wen, Djoko, Karrera Y., McEwan, Alastair G., Kobe, Bostjan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2016
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.
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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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