Do FeS clusters rule bacterial iron regulation?

Abstract

For decades, the bacterial ferric uptake regulator (Fur) has been thought to respond to ferrous iron to transcriptionally regulate genes required for balancing iron uptake, storage, and utilization. Because iron binding to Fur has never been confirmed in vivo, the physiological iron-sensing mechanism remains an open question. Fontenot et al. now show that Fur purified from Escherichia coli binds an all-Cys-coordinated [2Fe-2S] cluster. This finding opens the exciting possibility that Fur may join numerous well-studied bacterial, fungal, and mammalian proteins that use FeS clusters for cellular iron regulation.

Figure 1.

Simplified model for transcriptional regulation of iron homeostasis by bacterial Fur. a, the dimeric transcriptional ferric uptake regulator Fur can act in multiple ways to modulate gene expression (3). Upon binding to DNA promoter regions, holo-Fur acts as a repressor of genes for various iron uptake systems and the regulatory RNA rhyB (top right). Additionally, holo-Fur induces genes for iron storage and utilization (bottom right). The co-regulatory species of Fur that senses intracellular iron levels in vivo (indicated by a question mark) is not known with certainty yet. b, for a long time, ferrous iron (Fe²⁺) bound to histidine and acidic residues (site 2, left) was thought to be the iron sensor, yet the new study by Fontenot et al. provides evidence for an all-cysteine-bound [2Fe-2S] cluster (site 3, right) raising the exciting possibility that intracellular iron is sensed and regulated indirectly via FeS clusters. For simplicity, the cartoon omits the transcription-regulatory activity of apo-Fur lacking a bound iron cofactor.