Structure of a Wbl protein and implications for NO sensing by M. tuberculosis

Kudhair, Bassam K.; Hounslow, Andrea M.; Rolfe, Matthew D.; Crack, Jason C.; Hunt, Debbie M.; Buxton, Roger S.; Smith, Laura J.; Brun, Nick E. Le; Williamson, Michael P.; Green, Jeffrey

doi:10.1038/s41467-017-02418-y

Cited by 44 publications

(90 citation statements)

References 59 publications

(87 reference statements)

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“…) may be important for this interaction. In line with this, the WhiB1 Mtb ‐SigA interaction is dependent upon the presence of the [4Fe–4S] cluster and is disrupted under conditions of iron limitation or nitrosative stress (Kudhair et al , ). Since only apo‐WhiB1 has been shown to bind DNA, the significance of the interaction between holo‐WhiB1 and SigA requires further study.…”

Section: Class I (Whib1/wble/whce)mentioning

confidence: 85%

“…via nitrosylation) is required to make the C‐terminal helix available for interaction with DNA. In support of this, NMR of apo‐WhiB1 Mtb , prepared via nitrosylation, suggests a substantial conformational change upon addition of NO (Kudhair et al , ).…”

Section: Class I (Whib1/wble/whce)mentioning

confidence: 89%

“…As has been shown for other Wbl‐family members, WhiB4 contains an O 2 ‐ and NO‐sensitive [4Fe–4S] cluster (Alam et al , ; Chawla et al , ). However, the [4Fe–4S] cluster of WhiB4 Mtb appears to be more sensitive to O 2 than reported for other Wbls, such as WhiB3/WhiD (Singh et al , ; Crack et al , ) and WhiB1(Kudhair et al , ), suggesting a specific role for WhiB4 Mtb in redox‐sensing (Chawla et al , ). In line with this, holo‐WhiB4 Mtb is not competent to bind to DNA but the loss of the [4Fe–4S] cluster and oxidation of the coordinating cysteines strongly stimulates DNA binding.…”

Section: Class IV (Whib4/wbla/whca)mentioning

confidence: 91%

“…The [4Fe–4S] cluster of M. tuberculosis WhiB1 appears particularly O 2 ‐stable (Smith et al , ; Crack et al , ), facilitating the application of NMR to generate the first structure of a WhiB‐like protein (Kudhair et al , ). This model indicates the [4Fe–4S] cluster holds three α‐helices in place, generating a compact structure (Fig.…”

Section: Class I (Whib1/wble/whce)mentioning

confidence: 99%

“…The Structure of WhiB1 from Mycobacterium tuberculosis (Kudhair et al , ). Labelled are the four conserved Cysteine residues (C9, C37, C40 and C46), two Glycines (G61 and G62) that are part of the conserved G(V/I)WGG turn and the C‐terminal Arginine residues (R73 and R74) that are proposed to interact with DNA in M. tuberculosis .…”

Section: Class I (Whib1/wble/whce)mentioning

confidence: 99%

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The actinobacterial WhiB‐like (Wbl) family of transcription factors

Bush

2018

Molecular Microbiology

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SummaryThe WhiB‐like (Wbl) family of proteins are exclusively found in Actinobacteria. Wbls have been shown to play key roles in virulence and antibiotic resistance in Mycobacteria and Corynebacteria, reflecting their importance during infection by the human pathogens Mycobacterium tuberculosis, Mycobacterium leprae and Corynebacterium diphtheriae. In the antibiotic‐producing Streptomyces, several Wbls have important roles in the regulation of morphological differentiation, including WhiB, a protein that controls the initiation of sporulation septation and the founding member of the Wbl family. In recent years, genome sequencing has revealed the prevalence of Wbl paralogues in species throughout the Actinobacteria. Wbl proteins are small (generally ~80–140 residues) and each contains four invariant cysteine residues that bind an O2‐ and NO‐sensitive [4Fe–4S] cluster, raising the question as to how they can maintain distinct cellular functions within a given species. Despite their discovery over 25 years ago, the Wbl protein family has largely remained enigmatic. Here I summarise recent research in Mycobacteria, Corynebacteria and Streptomyces that sheds light on the biochemical function of Wbls as transcription factors and as potential sensors of O2 and NO. I suggest that Wbl evolution has created diversity in protein–protein interactions, [4Fe–4S] cluster‐sensitivity and the ability to bind DNA.

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Section: Class I (Whib1/wble/whce)mentioning

confidence: 85%

Section: Class I (Whib1/wble/whce)mentioning

confidence: 89%

Section: Class IV (Whib4/wbla/whca)mentioning

confidence: 91%

Section: Class I (Whib1/wble/whce)mentioning

confidence: 99%

Section: Class I (Whib1/wble/whce)mentioning

confidence: 99%

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The actinobacterial WhiB‐like (Wbl) family of transcription factors

Bush

2018

Molecular Microbiology

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Structure–Function Relationships of the NsrR and RsrR Transcription Regulators

Volbeda¹,

Crack²,

Brun³

2020

Encyclopedia of Inorganic and Bioinorganic Chemistry

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Protein‐coordinated iron–sulfur clusters play multiple crucial functions in biological processes. One of these functions is the response to effectors that regulate gene expression. This response can be very variable. Several members of the Rrf2 family of bacterial transcriptional regulators contain [FeS] clusters that perform a variety of sensing roles, including those involved in controlling cellular iron levels (RirA), controlling [FeS] cluster synthesis (IscR), responding to nitrosative stress (NsrR), and monitoring and possibly regulating the redox status of the cell (RsrR). Cluster ligation and composition varies significantly, and, with the exception of RsrR, DNA binding is regulated by effector‐dependent either partial or total cluster disassembly. Our own recent work has concentrated on the structure–function relationships of NsrR and RsrR, which coordinate [4Fe4S] and [2Fe2S] clusters, respectively. The reaction of nitric oxide with the NsrR [4Fe4S] cluster is progressive and modulates NsrR binding to different promotors. One consequence of cluster disassembly is the disruption of a key salt bridge that, in turn, causes a conformational change in the helix‐turn‐helix DNA‐binding domain of NsrR. The case of RsrR is especially interesting because its DNA binding depends on a one‐electron cluster redox change. This reduction causes the protonation of a neighboring His residue, which is followed by the generation of a protein cavity and the rotation of a tryptophan residue into it. Like in the case of NsrR, this rotation provokes a conformational change in the helix‐turn‐helix DNA‐binding domain of the protein.

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Sigma A‐bound iron–sulfur protein WhiB1 in Mycobacterium tuberculosis

Zhang

2021

Encyclopedia of Inorganic and Bioinorganic Chemistry

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WhiB1 belongs to the WhiB‐like family that is widely distributed in the phylum of Actinobacteria. It is a monomeric transcription factor that contains a [4Fe–4S] cluster in the holo‐form. In mycobacteria, the holo‐WhiB1 interacts with the domain 4 of the σ 70 ‐family primary sigma factor (σ A 4 ) in the RNA polymerase holoenzyme and plays an essential role in active cell growth. Domain 4 of the σ 70 ‐family primary sigma factors recognizes the −35 hexamer of promoter DNA and is commonly utilized by transcription factors for gene activation. However, the crystal structure of the WhiB1:σ A 4 complex reveals unexpectedly that WhiB1 binds to σ A 4 using a hydrophobic interface that differs markedly from previously characterized σ A 4 ‐bound bacterial transcription activators. Moreover, holo‐WhiB1 represses transcription by interaction with σ A 4 in vitro and WhiB1's essential role in supporting mycobacterial growth requires its interaction with σ A in vivo . Together, these results demonstrate that holo‐WhiB1 regulates gene expression by a noncanonical mechanism relative to well‐characterized σ A 4 ‐dependent transcription activators.

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Structure of a Wbl protein and implications for NO sensing by M. tuberculosis

Cited by 44 publications

References 59 publications

The actinobacterial WhiB‐like (Wbl) family of transcription factors

The actinobacterial WhiB‐like (Wbl) family of transcription factors

Structure–Function Relationships of the NsrR and RsrR Transcription Regulators

Sigma A‐bound iron–sulfur protein WhiB1 in Mycobacterium tuberculosis

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