Variation on a theme: investigating the structural repertoires used by ferric uptake regulators to control gene expression

Abstract

In every living organism, the control of metal homoeostasis is a tightly regulated process coordinated by several intertwined biological pathways. In many bacteria, the ferric uptake regulator (Fur) family of transcriptional factors (TFs) are key factors in controlling the expression of genes involved in metal homeostasis and can also regulate the expression of genes involved in responses to oxidative stresses. Since the crystallization of Escherichia coli Fur DNA binding domain, the crystal structure of several metalloregulators have been reported. While the Fur family of proteins adopt similar structures, each contains unique structural features relating to their specific biological functions. Moreover, recent groundbreaking studies have provided additional insights into the mechanisms underlying the binding of DNA by these metalloregulators. In this review, we present a comprehensive overview of the crystal structure of Fur family metalloregulators with a specific focus on the new structures of these TFs bound to DNA.

Allosteric control of metal-responsive transcriptional regulators in bacteria

“…The Fur family of transcriptional repressors-including Fe(II)-responsive Fur, Zn(II)-responsive Zur, Mn(II)-responsive Mur, and Ni(II)-responsive Nur-are widespread in bacteria and act as global regulators of many operons (Fig. 1B) (73)(74)(75). Metal binding activates DNA binding by the proteins in this family, which play important and diverse biological roles.…”

“…Metal binding activates DNA binding by the proteins in this family, which play important and diverse biological roles. For instance, Mur and Zur regulate the expression of the corresponding metal uptake systems, and Zur is known to regulate additional genes involved in Zn(II) homeostasis as well as protection from oxidative stress, whereas Fur is considered to be a global transcriptional regulator because it regulates the expression of various genes encoding proteins involved in Fe(II) homeostasis, DNA synthesis, energy metabolism, and many more (73,75).…”

“…Members of this family are typically homodimers with two winged-helix DBDs and metal-binding sites at the dimerization domain (73,75). These proteins generally bind two to three metal ions per monomer, including in many cases a Zn(II) ion required for folding and dimerization that is often referred to as the "structural" metal (73,76).…”

“…These proteins generally bind two to three metal ions per monomer, including in many cases a Zn(II) ion required for folding and dimerization that is often referred to as the "structural" metal (73,76). A key metal-sensing site is located near the hinge region that links the two domains and includes a conserved coordinating histidine (73,75,77,78). Metal binding to this site bridges both domains, drawing them in closer together, along with re-orientation of the N-terminal domains.…”

“…Initially classed as a metal-dependent repressor, Fur can also modulate transcriptional activation, and in some organisms there is evidence of direct genetic regulation by apo-protein (73,74). These complex modes of action may be modulated by the ability of Fur to compact the DNA structure (80), as well as variations between the structures of the different homologs (75). An additional means of regulation may arise through the quaternary structure of the proteins, given that a subclass of Fur homologs are isolated as tetramers in both the apo-and metalbound states (81,82).…”