Redox-sensing iron–sulfur cluster regulators

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Significance: Iron–sulfur cluster proteins carry out multiple functions, including as regulators of gene transcription/translation in response to environmental stimuli. In all known cases, the cluster acts as the sensory module, where the inherent reactivity/fragility of iron–sulfur clusters with small/redox-active molecules is exploited to effect conformational changes that modulate binding to DNA regulatory sequences. This promotes an often substantial reprogramming of the cellular proteome that enables the organism or cell to adapt to, or counteract, its changing circumstances.

Recent Advances: Significant progress has been made recently in the structural and mechanistic characterization of iron–sulfur cluster regulators and, in particular, the O2 and NO sensor FNR, the NO sensor NsrR, and WhiB-like proteins of Actinobacteria. These are the main focus of this review.

Critical Issues: Striking examples of how the local environment controls the cluster sensitivity and reactivity are now emerging, but the basis for this is not yet fully understood for any regulatory family.

Future Directions: Characterization of iron–sulfur cluster regulators has long been hampered by a lack of high-resolution structural data. Although this still presents a major future challenge, recent advances now provide a firm foundation for detailed understanding of how a signal is transduced to effect gene regulation. This requires the identification of often unstable intermediate species, which are difficult to detect and may be hard to distinguish using traditional techniques. Novel approaches will be required to solve these problems.
Original languageEnglish
Pages (from-to)1809-1829
Number of pages21
JournalAntioxidants & Redox Signaling
Issue number18
Early online date1 Oct 2017
Publication statusPublished - 1 Nov 2018


  • iron-sulfur
  • DNA regulator
  • O2
  • nitric oxide
  • redox stress

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