Human frataxin is an allosteric switch that activates the Fe-S cluster biosynthetic complex

Biochemistry. 2010 Nov 2;49(43):9132-9. doi: 10.1021/bi1013062.


Cellular depletion of the human protein frataxin is correlated with the neurodegenerative disease Friedreich's ataxia and results in the inactivation of Fe-S cluster proteins. Most researchers agree that frataxin functions in the biogenesis of Fe-S clusters, but its precise role in this process is unclear. Here we provide in vitro evidence that human frataxin binds to a Nfs1, Isd11, and Isu2 complex to generate the four-component core machinery for Fe-S cluster biosynthesis. Frataxin binding dramatically changes the K(M) for cysteine from 0.59 to 0.011 mM and the catalytic efficiency (k(cat)/K(M)) of the cysteine desulfurase from 25 to 7900 M⁻¹s⁻¹. Oxidizing conditions diminish the levels of both complex formation and frataxin-based activation, whereas ferrous iron further stimulates cysteine desulfurase activity. Together, these results indicate human frataxin functions with Fe(2+) as an allosteric activator that triggers sulfur delivery and Fe-S cluster assembly. We propose a model in which cellular frataxin levels regulate human Fe-S cluster biosynthesis that has implications for mitochondrial dysfunction, oxidative stress response, and both neurodegenerative and cardiovascular disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation*
  • Biological Transport
  • Carbon-Sulfur Lyases / metabolism
  • Humans
  • Iron / metabolism
  • Iron-Binding Proteins / metabolism
  • Iron-Binding Proteins / physiology*
  • Iron-Regulatory Proteins / metabolism
  • Iron-Sulfur Proteins / biosynthesis*
  • Mitochondrial Proteins
  • Multiprotein Complexes / physiology
  • Sulfur / metabolism


  • Iron-Binding Proteins
  • Iron-Regulatory Proteins
  • Iron-Sulfur Proteins
  • LYRM4 protein, human
  • Mitochondrial Proteins
  • Multiprotein Complexes
  • frataxin
  • Sulfur
  • Iron
  • Carbon-Sulfur Lyases
  • NFS1 protein, human
  • cysteine desulfurase