The Wbl proteins - a novel family of [4Fe-4S] cluster-containing transcription factors

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This grant seeks to understand the biological roles and regulation of a novel class of transcription factors that we have recently discovered carry a redox-active [4Fe-4S] cluster. The Wbl (WhiB-like) family of transcription factors is present throughout the actinomycetes, the family of bacteria that includes Streptomyces, the genus responsible for the production of two-thirds of the known antibiotics, as well as medically important pathogens such as Mycobacterium tuberculosis and Corynebacterium diphtheriae. Classical genetics has shown that Wbl proteins play pivotal and diverse roles in actinomycete biology. Two of the Wbl proteins that are the focus of attention in this grant are WhiB and WhiD, required, respectively, for the early and late stages of sporulation in Streptomyces coelicolor. The third is a remarkable and unique protein called WblP, which is an ECF sigma factor carrying a Wbl domain at its N-terminus. The [4Fe-4S] clusters of WhiD, WhiB and WblP are redox active, suggesting that their transcriptional activity, and hence the expression of the genes under their control, might be redox-regulated in vivo. Importantly, these experiments raise the possibility that Streptomyces sporulation might be redox-regulated, a totally novel and unexpected finding. To address these intriguing questions, we will identify the genes under control of these proteins, establish in vitro assays for their function, and investigate how the nature and redox state of the Fe-S cluster contributes to the biological function of Wbl proteins.

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