[2Fe-2S] cluster transfer in iron-sulfur protein biogenesis

Proc Natl Acad Sci U S A. 2014 Apr 29;111(17):6203-8. doi: 10.1073/pnas.1400102111. Epub 2014 Apr 14.


Monothiol glutaredoxins play a crucial role in iron-sulfur (Fe/S) protein biogenesis. Essentially all of them can coordinate a [2Fe-2S] cluster and have been proposed to mediate the transfer of [2Fe-2S] clusters from scaffold proteins to target apo proteins, possibly by acting as cluster transfer proteins. The molecular basis of [2Fe-2S] cluster transfer from monothiol glutaredoxins to target proteins is a fundamental, but still unresolved, aspect to be defined in Fe/S protein biogenesis. In mitochondria monothiol glutaredoxin 5 (GRX5) is involved in the maturation of all cellular Fe/S proteins and participates in cellular iron regulation. Here we show that the structural plasticity of the dimeric state of the [2Fe-2S] bound form of human GRX5 (holo hGRX5) is the crucial factor that allows an efficient cluster transfer to the partner proteins human ISCA1 and ISCA2 by a specific protein-protein recognition mechanism. Holo hGRX5 works as a metallochaperone preventing the [2Fe-2S] cluster to be released in solution in the presence of physiological concentrations of glutathione and forming a transient, cluster-mediated protein-protein intermediate with two physiological protein partners receiving the [2Fe-2S] cluster. The cluster transfer mechanism defined here may extend to other mitochondrial [2Fe-2S] target proteins.

Keywords: Fe/S protein maturation; NMR; [2Fe-2S] cluster transfer mechanism; monothiol Grxs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoproteins / chemistry
  • Apoproteins / metabolism
  • Glutaredoxins / chemistry
  • Glutaredoxins / metabolism
  • Glutathione / metabolism
  • Humans
  • Iron / metabolism*
  • Iron-Sulfur Proteins / chemistry
  • Iron-Sulfur Proteins / metabolism*
  • Magnetic Resonance Spectroscopy
  • Mitochondrial Proteins / chemistry
  • Mitochondrial Proteins / metabolism*
  • Models, Molecular
  • Protein Binding
  • Protein Structure, Quaternary
  • Solutions
  • Spectrophotometry, Ultraviolet
  • Sulfur / metabolism*


  • Apoproteins
  • Glutaredoxins
  • ISCA1 protein, human
  • Iron-Sulfur Proteins
  • Mitochondrial Proteins
  • Solutions
  • Sulfur
  • Iron
  • Glutathione

Associated data

  • PDB/2MMZ