Ferric uptake regulator family

Function

Members of the ferric uptake regulator family are transcription factors that primarily exert their regulatory effects as repressors: when bound to their cognate metal ion, they are capable of binding DNA and preventing expression of the genes they regulate, but under low concentrations of metal, they undergo a conformational change that prevents DNA binding and lifts the repression. In the case of the ferric uptake regulator protein itself, its immediate downstream target is a noncoding RNA called RyhB.

The Ferric Uptake Regulator protein functions in Gram-negative and Gram-positive bacteria. Ferric uptake regulators act by sensing changes in free iron, so upon activation, they regulate target genes through interactions with the promoter region, known as the "Fur box". The magnetospirillum gryphiswaldense MSR-1 Fur is a key regulatory protein involved in maintaining iron homeostasis. This Fur is similar to the E. coli Fur, which acts by binding to Fur boxes to regulate gene expression as a way to maintain iron levels. Additionally, it serves as a model and foundation for other regulators that are able to sense changes in iron, zinc, and magnesium.

In the image of the binding sites of magnetospirillum gryphiswaldense, the cyan color reflects the glutamate residues, while the magenta represents the histidine residues. These residues interact with the manganese ion to create binding site 1 in the ferric uptake regulator protein.

In addition to the ferric uptake regulator protein, members of the Fur family are also involved in maintaining homeostasis with respect to other ions:

• Mur, responsive to manganese.
• Nur, responsive to nickel.
• PerR, responsive to peroxide; PerR monomers contain two binding sites and occur in zinc/iron and zinc/manganese forms.
• Zur, responsive to zinc; Zur regulates uptake and transport through a regulon involving ZinT and the transporter ZnuABC.
• Irr, responsive to iron through the status of heme biosynthesis. Has both activator and repressor function. Prevalent in Rhizobium, Bradyrhizobium and many other alphaproteobacteria.

The iron dependent repressor family is a functionally similar but non-homologous family of proteins involved in iron homeostasis in prokaryotes.

Relationship to virulence

Metal homeostasis can be a factor in bacterial virulence, an observation with a particularly long history in the case of iron. In some cases, expression of virulence factors is under the regulatory control of the Fur protein.

References

References

1. (February 2003). "Architecture of a protein central to iron homeostasis: crystal structure and spectroscopic analysis of the ferric uptake regulator". Molecular Microbiology.
2. (August 2015). "Interplay between iron homeostasis and virulence: Fur and RyhB as major regulators of bacterial pathogenicity". Veterinary Microbiology.
3. (November 2014). "Structural and mechanistic basis of zinc regulation across the E. coli Zur regulon". PLOS Biology.
4. (January 2009). "How do bacterial cells ensure that metalloproteins get the correct metal?". Nature Reviews. Microbiology.
5. (May 2004). "The Fur-like protein Mur of Rhizobium leguminosarum is a Mn(2+)-responsive transcriptional regulator". Microbiology.
6. (July 2004). "Fur is involved in manganese-dependent regulation of mntA (sitA) expression in Sinorhizobium meliloti". Applied and Environmental Microbiology.
7. (June 2004). "The Sinorhizobium meliloti fur gene regulates, with dependence on Mn(II), transcription of the sitABCD operon, encoding a metal-type transporter". Journal of Bacteriology.
8. (April 2009). "The mntH gene encodes the major Mn(2+) transporter in Bradyrhizobium japonicum and is regulated by manganese via the Fur protein". Molecular Microbiology.
9. (February 2012). "Mur regulates the gene encoding the manganese transporter MntH in Brucella abortus 2308". Journal of Bacteriology.
10. (March 2006). "Nur, a nickel-responsive regulator of the Fur family, regulates superoxide dismutases and nickel transport in Streptomyces coelicolor". Molecular Microbiology.
11. (March 2006). "The PerR transcription factor senses H2O2 by metal-catalysed histidine oxidation". Nature.
12. (July 2009). "Severe zinc depletion of Escherichia coli: roles for high affinity zinc binding by ZinT, zinc transport and zinc-independent proteins". The Journal of Biological Chemistry.
13. (March 2015). "Advances in the molecular understanding of biological zinc transport". Chemical Communications.
14. (2015). "Perception and Homeostatic Control of Iron in the Rhizobia and Related Bacteria". Annual Review of Microbiology.
15. (1978). "Modern Aspects of Electrochemistry".
16. (2000). "Iron metabolism in pathogenic bacteria". Annual Review of Microbiology.