Selective Gene Regulation by Manganese and Iron in Bacillus subtilis

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All organisms must obtain a specific set of trace metals from their environment. Accordingly, cells must be able to sense the intracellular level of individual metal ions in order to properly coordinate metal ion transport, storage, and intracellular trafficking. Cellular metal ion levels are monitored by metalloregulatory proteins that repress or activate the expression of metal ion homeostasis genes. In Bacillus subtilis, four distinct metalloregulators control the transport of zinc, iron, and manganese and regulate an oxidative stress response. This project addresses the biological roles and mechanisms of two regulators, the Fur and PerR proteins. The ferric uptake repressor (Fur) protein coordinates the expression of iron uptake functions by acting as an iron-dependent repressor. However, recent biochemical studies indicate that Fur binds tightly to its target operator sites independently of iron. This suggests that in the cell the activity of Fur is regulated by other factors, perhaps a metal ion, that antagonize this intrinsic DNA-binding activity. The peroxide regulon (PerR) repressor is structurally related to Fur. However, PerR functions physiologically as a sensor of oxidative stress, rather than metal ion starvation. It is proposed that PerR, together with a metal bound cofactor, reacts with hydrogen peroxide to generate an inactive repressor. The nature of the change(s) in PerR that lead to derepression are currently unknown. In this project, the molecular basis for Fe-sensing, by Fur, and peroxide-sensing, by PerR, will be investigated using a combination of molecular genetic and biochemical approaches. These studies will provide insights into how proteins bind selectively to different metal ions in the cell and how they can use metal ions to serve as sensors of oxidative stress. The presence of related regulators in diverse bacteria argues that the paradigms established by a detailed characterization of the B. subtilis regulators will have far-reaching implications.