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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

Structural basis of thiol-based regulation of formaldehyde detoxification in H. influenzae by a MerR regulator with no sensor region Thumbnail


Authors

Rafael M. Couñago

Nathan H. Chen

Chiung-Wen Chang

Alastair G. McEwan

Bostjan Kobe



Abstract

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.

Citation

Couñago, R. M., Chen, N. H., Chang, C., Djoko, K. Y., McEwan, A. G., & Kobe, B. (2016). Structural basis of thiol-based regulation of formaldehyde detoxification in H. influenzae by a MerR regulator with no sensor region. Nucleic Acids Research, 44(14), 6981-6993. https://doi.org/10.1093/nar/gkw543

Journal Article Type Article
Acceptance Date Jun 3, 2016
Online Publication Date Jun 15, 2016
Publication Date Aug 19, 2016
Deposit Date Sep 6, 2017
Publicly Available Date Oct 17, 2017
Journal Nucleic Acids Research
Print ISSN 0305-1048
Electronic ISSN 1362-4962
Publisher Oxford University Press
Peer Reviewed Peer Reviewed
Volume 44
Issue 14
Pages 6981-6993
DOI https://doi.org/10.1093/nar/gkw543

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http://creativecommons.org/licenses/by-nc/4.0/

Copyright Statement
© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research. 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







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