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The oxidation-sensing regulator (MosR) is a new redox-dependent transcription factor in Mycobacterium tuberculosis.

ABSTRACT: Mycobacterium tuberculosis thrives in oxidative environments such as the macrophage. To survive, the bacterium must sense and adapt to the oxidative conditions. Several antioxidant defenses including a thick cell wall, millimolar concentrations of small molecule thiols, and protective enzymes are known to help the bacterium withstand the oxidative stress. However, oxidation-sensing regulators that control these defenses have remained elusive. In this study, we report a new oxidation-sensing regulator, Rv1049 or MosR (M. tuberculosis oxidation-sensing regulator). MosR is a transcriptional repressor of the MarR family, which, similarly to Bacillus subtilis OhrR and Staphylococcus aureus MgrA, dissociates from DNA in the presence of oxidants, enabling transcription. MosR senses oxidation through a pair of cysteines near the N terminus (Cys-10 and Cys-12) that upon oxidation forms a disulfide bond. Disulfide formation rearranges a network of hydrogen bonds, which leads to a large conformational change of the protein and dissociation from DNA. MosR has been shown previously to play an important role in survival of the bacterium in the macrophage. In this study, we show that the main role of MosR is to up-regulate expression of rv1050 (a putative exported oxidoreductase that has not yet been characterized) in response to oxidants and propose that it is through this role that MosR contributes to the bacterium survival in the macrophage.

SUBMITTER: Brugarolas P

PROVIDER: S-EPMC3488046 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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The oxidation-sensing regulator (MosR) is a new redox-dependent transcription factor in Mycobacterium tuberculosis.

Brugarolas Pedro P Movahedzadeh Farahnaz F Wang Yuehong Y Zhang Nan N Bartek Iona L IL Gao Yihe N YN Voskuil Martin I MI Franzblau Scott G SG He Chuan C

The Journal of biological chemistry 20120918 45

Mycobacterium tuberculosis thrives in oxidative environments such as the macrophage. To survive, the bacterium must sense and adapt to the oxidative conditions. Several antioxidant defenses including a thick cell wall, millimolar concentrations of small molecule thiols, and protective enzymes are known to help the bacterium withstand the oxidative stress. However, oxidation-sensing regulators that control these defenses have remained elusive. In this study, we report a new oxidation-sensing regu ...[more]

PMID: 22992749

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Project description:BackgroundMembers of the WhiB-like (Wbl) protein family possess iron-sulfur clusters and are implicated in the regulation of developmental processes in Actinomycetes. Mycobacterium tuberculosis possesses seven Wbl proteins. The [4Fe-4S] cluster of M. tuberculosis WhiB1 is relatively insensitive to O(2) but very sensitive to nitric oxide (NO). Nitric oxide nitrosylates the WhiB1 iron-sulfur cluster and promotes DNA-binding; the apo-forms of WhiB1 also bind DNA. However, the molecular requirements for iron-sulfur cluster acquisition and for DNA-binding by WhiB1 are poorly characterized.Methods and findingsWhiB1 variants were created by site-directed mutagenesis and the abilities of the corresponding proteins to acquire an iron-sulfur cluster and/or bind to whiB1 promoter DNA were assessed. All four Cys residues (Cys9, 37, 40, and 46) in the N-terminal region of WhiB1 were required for incorporation of a [4Fe-4S] cluster, whereas a possible alternative cluster ligand Asp13 (by analogy with M. smegmatis WhiB2) was not. The C-terminal region of WhiB1 is predicted to house the DNA-binding domain of the protein consisting of a predicted ?-turn ((58)GVWGG(62)) followed by two amino acid motifs ((72)KRRN(75) and (78)TKAR(81)) that are conserved in WhiB1 proteins. Gly residues (Gly58, 61 and 62) in the ?-turn and positively-charged residues (Lys72, Arg73, Arg74, Lys79 and Arg81) in the downstream conserved regions were required for binding of WhiB1 DNA.ConclusionsSite-directed mutagenesis of M. tuberculosis whiB1 and characterization of the corresponding proteins has been used to explore structure-function relationships of the NO-responsive transcription factor WhiB1. This showed that all four conserved Cys residues in the N-terminal region are required for incorporation of iron-sulfur clusters but not for DNA-binding. Analysis of variants with amino acid substitutions in the C-terminal region revealed the crucial roles played by a predicted ?-turn and two conserved positively-charged motifs in facilitating DNA-binding, but not iron-sulfur cluster acquisition, by WhiB1.

Dataset Information

The oxidation-sensing regulator (MosR) is a new redox-dependent transcription factor in Mycobacterium tuberculosis.

Publications

The oxidation-sensing regulator (MosR) is a new redox-dependent transcription factor in Mycobacterium tuberculosis.

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