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Abstract
Mycobacterium tuberculosis causes pulmonary tuberculosis (TB) and claims ~1.8 million human lives per annum. Host nitric oxide (NO) is important in controlling TB infection. M. tuberculosis WhiB1 is a NO-responsive Wbl protein (actinobacterial iron–sulfur proteins first identified in the 1970s). Until now, the structure of a Wbl protein has not been available. Here a NMR structural model of WhiB1 reveals that Wbl proteins are four-helix bundles with a core of three α-helices held together by a [4Fe-4S] cluster. The iron–sulfur cluster is required for formation of a complex with the major sigma factor (σA) and reaction with NO disassembles this complex. The WhiB1 structure suggests that loss of the iron–sulfur cluster (by nitrosylation) permits positively charged residues in the C-terminal helix to engage in DNA binding, triggering a major reprogramming of gene expression that includes components of the virulence-critical ESX-1 secretion system.
Highlights
Mycobacterium tuberculosis causes pulmonary tuberculosis (TB) and claims ~1.8 million human lives per annum
The isolation of M. tuberculosis WhiB1 with a [4Fe-4S] cluster that was stable for several weeks in air permitted the determination of the structure of a white B-like (Wbl) protein
Wbl proteins have been extensively studied since their discovery more than 40 years ago because of their roles in regulating fundamental aspects of actinobacterial biology, including developmental processes and virulence
Summary
Mycobacterium tuberculosis causes pulmonary tuberculosis (TB) and claims ~1.8 million human lives per annum. The WhiB1 structure suggests that loss of the iron–sulfur cluster (by nitrosylation) permits positively charged residues in the C-terminal helix to engage in DNA binding, triggering a major reprogramming of gene expression that includes components of the virulence-critical ESX-1 secretion system. The fundamental role of Wbl proteins in developmental processes in Actinobacteria suggested that they could play a role in entry into and emergence from the non-replicative persistent state that is characteristic of M. tuberculosis infections. M. tuberculosis possesses seven genes encoding Wbl proteins and several of these have been implicated in features of TB pathogenesis such as persistence (WhiB3), antibiotic resistance (WhiB7), and the regulation of lipid and polyketide biosynthesis, including triacylglycerol accumulation as a response to hypoxia and nitrosative stress in macrophages (WhiB3)[14,15,16,17,18]. Structure–function studies have shown that all four cysteine residues of WhiB1 are required for iron–sulfur cluster incorporation and that DNA binding by apo- or nitrosylated-WhiB1 requires positively charged residues in the C-terminal region[23]
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