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Review
. 2014 Apr:133:118-26.
doi: 10.1016/j.jinorgbio.2013.11.003. Epub 2013 Nov 15.

Insights into redox sensing metalloproteins in Mycobacterium tuberculosis

Nicholas Chim  1 , Parker M Johnson  1 , Celia W Goulding  2
Affiliations
Review

Insights into redox sensing metalloproteins in Mycobacterium tuberculosis

Nicholas Chim et al. J Inorg Biochem. 2014 Apr.

Abstract

Mycobacterium tuberculosis, the pathogen that causes tuberculosis, has evolved sophisticated mechanisms for evading assault by the human host. This review focuses on M. tuberculosis regulatory metalloproteins that are sensitive to exogenous stresses attributed to changes in the levels of gaseous molecules (i.e., molecular oxygen, carbon monoxide and nitric oxide) to elicit an intracellular response. In particular, we highlight recent developments on the subfamily of Whi proteins, redox sensing WhiB-like proteins that contain iron-sulfur clusters, sigma factors and their cognate anti-sigma factors of which some are zinc-regulated, and the dormancy survival regulon DosS/DosT-DosR heme sensory system. Mounting experimental evidence suggests that these systems contribute to a highly complex and interrelated regulatory network that controls M. tuberculosis biology. This review concludes with a discussion of strategies that M. tuberculosis has developed to maintain redox homeostasis, including mechanisms to regulate endogenous nitric oxide and carbon monoxide levels.

Keywords: Hypoxia; Metalloproteins; Molecular gas sensing; Mycobacterium tuberculosis; Redox sensing.

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Figures

Figure 1
Figure 1
Transcriptional factor regulatory subnetwork linking hypoxia, lipid metablosim and protein degradation. Grey arrows pointing down or up indicate gene down- or up-regulation, respectively, under hypoxic conditions. Grey lines represent correlated activation or repression between genes.
Figure 2
Figure 2
The proposed mechanism of Wbl activation. Under the current model, the [4Fe-4S] cluster bound to the Wbl proteins degrade via a series of intermediates upon exposure to NO and O2. The resulting conserved cysteine residues oxidize to form disulfide bonds and the apo-Wbl proteins are then able to bind to their respective DNA promoter regions to regulate transcription or perform their disulfide reductase activity. The oligomeric states of the Wbl proteins remain to be elucidated.
Figure 3
Figure 3
The mechanism of SigL regulation. The membrane-associated anti-σ factor, RslA, contains a conserved cytosolic ZAS (HXXXCXXC) motif, which coordinates a structural Zn2+ ion under reducing conditions. SigL function is inhibited through complex formation occluding SigL’s predicted -35 promoter binding domain (PDB code 3HUG). Upon exposure to oxidative stress, the two cysteines of the CXXC motif (Cys54 and Cys57) form a disulfide bond, releasing the Zn2+ ion and leading to a conformational change in RslA. This conformational change results in the dissociation of the RslA/SigL complex, allowing SigL to interact with RNA polymerase and upregulate target genes.
Figure 4
Figure 4
Structures of DosS and DosT. Molecular surface representation for A & C, with a grey ribbon model and important residues in stick representation where oxygen and nitrogen are colored red and blue, respectively, and DosS and DosT carbons are pink and cyan, respectively. (A) Active site of DosS (PDB code 2W3E) with a H-bonding network from heme to protein surface that does not allow access of gases to the heme-iron distal site due in part to Glu87. (B) Superimposition of DosS and DosT where important residues and heme molecules are in stick representation. (C) Active site of DosT (PDB code 2VZW) where Gly85, which is in the equivalent position of DosS Glu87, opens a channel for gases to access the distal position of heme-iron.
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