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Review
. 2012 Nov 1;17(9):1215-31.
doi: 10.1089/ars.2012.4511. Epub 2012 Mar 6.

Bacterial iron-sulfur regulatory proteins as biological sensor-switches

Jason C Crack  1 , Jeffrey Green, Matthew I Hutchings, Andrew J Thomson, Nick E Le Brun
Affiliations
Review

Bacterial iron-sulfur regulatory proteins as biological sensor-switches

Jason C Crack et al. Antioxid Redox Signal. .

Abstract

Significance: In recent years, bacterial iron-sulfur cluster proteins that function as regulators of gene transcription have emerged as a major new group. In all cases, the cluster acts as a sensor of the environment and enables the organism to adapt to the prevailing conditions. This can range from mounting a response to oxidative or nitrosative stress to switching between anaerobic and aerobic respiratory pathways. The sensitivity of these ancient cofactors to small molecule reactive oxygen and nitrogen species, in particular, makes them ideally suited to function as sensors.

Recent advances: An important challenge is to obtain mechanistic and structural information about how these regulators function and, in particular, how the chemistry occurring at the cluster drives the subsequent regulatory response. For several regulators, including FNR, SoxR, NsrR, IscR, and Wbl proteins, major advances in understanding have been gained recently and these are reviewed here.

Critical issues: A common theme emerging from these studies is that the sensitivity and specificity of the cluster of each regulatory protein must be exquisitely controlled by the protein environment of the cluster.

Future directions: A major future challenge is to determine, for a range of regulators, the key factors for achieving control of sensitivity/specificity. Such information will lead, eventually, to a system understanding of stress response, which often involves more than one regulator.

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Figures

FIG. 1.
FIG. 1.
Iron–sulfur clusters common in nature. Structures of [2Fe-2S], [3Fe-4S], and [4Fe-4S] iron–sulfur clusters. Iron, sulfide, and cysteine residues are indicated.
FIG. 2.
FIG. 2.
A model of Escherichia coli fumarate and nitrate reduction (FNR) regulator and its reaction with O2. The FNR model is based on the structure of E. coli catabolite repressor protein (CRP) [pdb file 1CGP (126)]. The [4Fe-4S] cluster is represented by a cube. After the increase in O2 concentration, the DNA-bound dimer FNR protein undergoes reaction at its cluster, resulting in a [2Fe-2S] form (represented by a rhomb) that dissociates into monomers and no longer binds DNA.
FIG. 3.
FIG. 3.
The chemistry of FNR cluster conversion. Scheme summarizing the mechanism of the reaction of [4Fe-4S] FNR with O2. See section Fumarate and nitrate reduction regulator for details.
FIG. 4.
FIG. 4.
Structure of [2Fe-2S] SoxR and its regulatory mechanism. (A) Structure of the SoxR monomer, with the dimerisation helix, DNA-binding domain, and [2Fe-2S] cluster indicated in sticks representation [pdb file 2ZHH (160)]. (B) Structure of SoxR bound to DNA (pdb file 2ZHG). Note that the cluster is represented in space-filling mode to ensure contrast with DNA, which is in sticks representation. (C) Scheme summarizing the SoxRS system in E. coli. Nonenteric bacteria do not contain SoxS and so SoxR itself directly regulates the Sox regulon. See section SoxR for details.
FIG. 5.
FIG. 5.
Structure of the Rrf2 family regulator CymR. Structure of the Bacillus subtilis CymR monomer, showing the dimerization helix and DNA-binding domain [pdb file 2Y75 (133)]. The likely location of cluster-binding cysteine residues found in homologous iron–sulfur cluster-binding Rrf2 proteins (e.g., IscR, NsrR, and RirA) is indicated.
FIG. 6.
FIG. 6.
Iron-nitrosyl species. (A) The reaction of iron–sulfur clusters in regulatory proteins has been reported to result in the formation of at least two different iron-nitrosyl species: dinitrosyl iron complex (DNIC) and Roussin's red ester (RRE). The formation of a novel tetranuclear iron octanitrosyl cluster species was recently discussed (27). (B) A scheme illustrating the reaction of WhiB-like (Wbl) [4Fe-4S]2+ clusters with nitric oxide (NO) (27, 139).
FIG. 7.
FIG. 7.
NsrR regulatory systems. Scheme summarizing the mechanism of NsrR NO-sensing and regulation. Specific DNA binding has been reported for NsrR proteins from different organisms in which the form of the cluster ([4Fe-4S] or [2Fe-2S]) is different (85, 153). The gene hmpA encodes an NO-detoxifying enzyme. Note that the high-resolution structure of NsrR is not yet available, and the schematic representation included here is based on the recently published structure of the Rrf2 family protein CymR (133). Structural information on the likely iron–nitrosyl species formed following reaction of NsrR with NO is given in Figure 6. Although not illustrated, apo-NsrR has also been reported to bind DNA (at a different sequence) and, therefore, may also fulfill a regulatory function (85).
FIG. 8.
FIG. 8.
The IscR regulatory system. Scheme summarizing the mechanism of IscR regulation of isc and suf operons. Under iron replete conditions (upper part of the figure), and when the cellular supply of iron–sulfur clusters is sufficient, cluster-bound IscR represses the housekeeping Isc iron–sulfur biogenesis system in E. coli. When iron–sulfur cluster demand increases, the apo-form of IscR accumulates, leading to depression of the cluster biosynthesis system. Under conditions of low iron or oxidative stress (lower part of the figure), E. coli utilizes a different iron–sulfur biogenesis system encoded by the Suf system. Under inducing conditions, suf operon expression is activated by apo-IscR, which accumulates under conditions of low iron–sulfur cluster supply through both the loss of cluster from cluster-bound IscR and depression of the isc operon, which includes iscR. See section IscR for details. Note that the high-resolution structure of IscR is not yet available, and the schematic representation included here is based on the recently published structure of the Rrf2 family protein CymR (133).
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