The unique regulation of iron-sulfur cluster biogenesis in a Gram-positive bacterium

Proc Natl Acad Sci U S A. 2014 Jun 3;111(22):E2251-60. doi: 10.1073/pnas.1322728111. Epub 2014 May 20.


Iron-sulfur clusters function as cofactors of a wide range of proteins, with diverse molecular roles in both prokaryotic and eukaryotic cells. Dedicated machineries assemble the clusters and deliver them to the final acceptor molecules in a tightly regulated process. In the prototypical Gram-negative bacterium Escherichia coli, the two existing iron-sulfur cluster assembly systems, iron-sulfur cluster (ISC) and sulfur assimilation (SUF) pathways, are closely interconnected. The ISC pathway regulator, IscR, is a transcription factor of the helix-turn-helix type that can coordinate a [2Fe-2S] cluster. Redox conditions and iron or sulfur availability modulate the ligation status of the labile IscR cluster, which in turn determines a switch in DNA sequence specificity of the regulator: cluster-containing IscR can bind to a family of gene promoters (type-1) whereas the clusterless form recognizes only a second group of sequences (type-2). However, iron-sulfur cluster biogenesis in Gram-positive bacteria is not so well characterized, and most organisms of this group display only one of the iron-sulfur cluster assembly systems. A notable exception is the unique Gram-positive dissimilatory metal reducing bacterium Thermincola potens, where genes from both systems could be identified, albeit with a diverging organization from that of Gram-negative bacteria. We demonstrated that one of these genes encodes a functional IscR homolog and is likely involved in the regulation of iron-sulfur cluster biogenesis in T. potens. Structural and biochemical characterization of T. potens and E. coli IscR revealed a strikingly similar architecture and unveiled an unforeseen conservation of the unique mechanism of sequence discrimination characteristic of this distinctive group of transcription regulators.

Keywords: DNA recognition; Rrf2-like regulator; helix-turn-helix motif; specificity modulation; transcription regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • DNA, Bacterial / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Dimerization
  • Escherichia coli K12 / genetics
  • Escherichia coli K12 / metabolism*
  • Escherichia coli Proteins / genetics
  • Escherichia coli Proteins / metabolism*
  • Gene Expression Regulation, Bacterial
  • Gram-Positive Bacteria / genetics
  • Gram-Positive Bacteria / metabolism*
  • Helix-Turn-Helix Motifs
  • Iron-Sulfur Proteins / genetics
  • Iron-Sulfur Proteins / metabolism*
  • Point Mutation
  • Promoter Regions, Genetic
  • Protein Structure, Tertiary
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • DNA, Bacterial
  • DNA-Binding Proteins
  • Escherichia coli Proteins
  • Iron-Sulfur Proteins
  • IscR protein, E coli
  • Transcription Factors

Associated data

  • PDB/4CHU
  • PDB/4CIC