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Cited by 62Bacterial Genetics and BiotechnologyIron Metabolism and DisordersMetalloenzymes and iron-sulfur proteins

Origins of specificity and cross‐talk in metal ion sensing by B acillus subtilisFur

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Ma, Zhen, Faulkner, Melinda J., Helmann, John D.·2012·Molecular Microbiology
DOI 10.1111/mmi.12049PMC PMC3508374
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Abstract

Summary: Fur (f erric u ptake r egulator) is the master regulator of iron homeostasis in many bacteria, but how it responds specifically to Fe(II) in vivo is not clear. Biochemical analyses of B acillus subtilis Fur (BsFur) reveal that in addition to Fe(II), both Z n(II) and Mn(II) allosterically activate BsFur–DNA binding. Dimeric BsFur co‐purifies with site 1 structural Zn(II) (Fur2Zn2) and can bind four additional Zn(II) or Mn(II) ions per dimer. Metal ion binding at previously described site 3 occurs with highest affinity, but the Fur2Zn2:Me2 form has only a modest increase in DNA binding affinity (approximately sevenfold). Metallation of site 2 (Fur2Zn2:Me4) leads to a ∼ 150‐fold further enhancement in DNA binding affinity. Fe(II) binding studies indicate that BsFur buffers the intracellular F e(II) concentration at ∼ 1 μ M. Both Mn(II) and Zn(II) are normally buffered at levels insufficient for metallation of BsFur site 2, thereby accounting for the lack of cross‐talk observed in vivo. However, in a perR mutant, where the BsFur concentration is elevated, BsFur may now use Mn(II) as a co‐repressor and inappropriately repress iron uptake. Since PerR repression of fur is enhanced by Mn(II), and antagonized by Fe(II), PerR may co‐regulate F e(II) homeostasis by modulating BsFur levels in response to the Mn(II)/Fe(II) ratio.

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Crossref · 10.1111/mmi.12049

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  • Some iron-binding enzymes behave more as iron-activated enzymes rather than stable metalloproteins, and Fur is unusually abundant and could also function as an Fe2+-buffering protein.

    “Some iron-binding enzymes behave more as iron-activated enzymes rather than stable metalloproteins,148 and Fur is unusually abundant for a regulator and could also function as an Fe2+-buffering protein.101”

    From Metals in Motion: Understanding Labile Metal Pools in Bacteria (2025) · cites this paper as [101]

    Citation 101 attaches to the Fur clause, not the preceding claim about iron-binding enzymes. The Abstract says BsFur buffers intracellular Fe(II) at approximately 1 μM, supporting the proposed buffering role. Our copy discusses elevated Fur levels in a perR mutant, but does not establish that Fur is unusually abundant compared with other regulators. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Best estimates of the labile manganese pool in model bacteria derive from measurements of the amount of free Mn2+ required for regulation of gene expression by Mn2+-dependent regulators such as MntR and Mn2+-dependent riboswitches.

    “Our current best estimates of the labile manganese pool in model bacteria derive from measurements of the amount of free Mn2+ required for regulation of gene expression by Mn2+-dependent regulators such as the MntR transcription factor101,102 and Mn2+-dependent riboswitches.103”

    From Metals in Motion: Understanding Labile Metal Pools in Bacteria (2025) · cites this paper as [101]

  • Fur binds Fe2+ with a Kd of 1.2 μM in E. coli and 0.8 μM in B. subtilis, and even lower levels suffice to stabilize DNA-binding due to additional coupling free energy.

    “The ferric uptake repressor (Fur; Figure 2) binds Fe2+ with an affinity (Kd) of 1.2 μM in E. coli(141) and 0.8 μM in B. subtilis, and even lower levels suffice to stabilize DNA-binding due to the additional coupling free energy.101”

    From Metals in Motion: Understanding Labile Metal Pools in Bacteria (2025) · cites this paper as [101]

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Cites

Flagged first, then by citations

Research works printed but not linked: 28

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Authors
Ma, Z., Faulkner, M. J., & Helmann, J. D.
Affiliations
Cornell University (US)
Corresponding author
Helmann, John D.
ORCID
Venue
Molecular Microbiology
Publisher
Wiley
Published
2012-10-12
Volume
86
Issue
5
Pages
1144-1155
ISSN
  • 0950-382X (ISSN-L)
  • 1365-2958
DOI
10.1111/mmi.12049
PMC
PMC3508374
OpenAlex
W1494129769
Cited by
62
References
11
Citations by year
2025: 3 · 2024: 7 · 2023: 3 · 2022: 3 · 2021: 1 · 2020: 7 · 2019: 3 · 2018: 4 · 2017: 7 · 2016: 7 · 2015: 4 · 2014: 8 · 2013: 5
FWCI
3.26
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Molecular Microbiology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute of General Medical Sciences (GM059323, R01GM059323)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Physical Sciences › Energy › Renewable Energy, Sustainability and the Environment › Metalloenzymes and iron-sulfur proteins
Keywords
Fur protein, ferric uptake regulator, Bacillus subtilis, iron homeostasis, metal ion sensing, allosteric activation, zinc binding, manganese binding, DNA binding affinity, PerR, transcriptional regulation
MeSH terms
Bacillus subtilis, Bacterial Proteins, Binding Sites, Ferrous Compounds, Homeostasis, Iron, Manganese, Protein Binding, Repressor Proteins, Zinc, Gene Expression Regulation, Bacterial

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