Characterization of human glutaredoxin 2 as iron-sulfur protein

A possible role as red ox sensor

Christopher Horst Lillig, Carsten Berndt, Olivia M. Vergnolle, Maria Elisabet Lönn, Christoph Hudemann, Eckhard Bill, Arne Holmgren

Research output: Contribution to journalArticle

195 Citations (Scopus)

Abstract

Human mitochondrial glutaredoxin 2 (Grx2) is a glutathione-dependent oxidoreductase (active site: Cys-Ser-Tyr-Cys) that facilitates the maintenance of mitochondrial redox homeostasis upon induction of apoptosis by oxidative stress. Here, we have characterized Grx2 as an iron-sulfur center-containing member of the thioredoxin fold protein family. Mössbauer spectroscopy revealed the presence of a four cysteine-coordinated nonoxidizable [2Fe-2S] 2+ cluster that bridges two Grx2 molecules via two structural Cys residues to form dimeric holo Grx2. Coimmunoprecipitation of radiolabeled iron with Grx2 from human cell lines indicated the presence of the cluster in vivo. The [2Fe-2S]-bridged dimer was enzymatically inactive, but degradation of the cluster and the resulting monomerization of Grx2 activated the protein. Slow degradation under aerobic conditions was prevented by the presence of glutathione, whereas glutathione disulfide as well as one-electron oxidants or reductants promoted monomerization of Grx2. We propose that the iron-sulfur cluster serves as a redox sensor for the activation of Grx2 during conditions of oxidative stress when free radicals are formed and the glutathione pool becomes oxidized.

Original languageEnglish (US)
Pages (from-to)8168-8173
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number23
DOIs
StatePublished - Jun 7 2005
Externally publishedYes

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Glutaredoxins
Iron-Sulfur Proteins
Staphylococcal Protein A
Glutathione
Iron
Sulfur
Oxidation-Reduction
Oxidative Stress
Thioredoxins
Glutathione Disulfide
Reducing Agents
Oxidants
Free Radicals
Cysteine
Catalytic Domain
Spectrum Analysis
Oxidoreductases
Proteins
Homeostasis
Maintenance

Keywords

  • Glutathione
  • Iron-sulfur cluster
  • Mitochondria
  • Oxidative stress
  • Thiol disulfide oxidoreductase

ASJC Scopus subject areas

  • General

Cite this

Characterization of human glutaredoxin 2 as iron-sulfur protein : A possible role as red ox sensor. / Lillig, Christopher Horst; Berndt, Carsten; Vergnolle, Olivia M.; Lönn, Maria Elisabet; Hudemann, Christoph; Bill, Eckhard; Holmgren, Arne.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 23, 07.06.2005, p. 8168-8173.

Research output: Contribution to journalArticle

Lillig, Christopher Horst ; Berndt, Carsten ; Vergnolle, Olivia M. ; Lönn, Maria Elisabet ; Hudemann, Christoph ; Bill, Eckhard ; Holmgren, Arne. / Characterization of human glutaredoxin 2 as iron-sulfur protein : A possible role as red ox sensor. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 23. pp. 8168-8173.
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