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Intermolecular disulfide bond formation in the NEMO dimer requires Cys54 and Cys347.

NEMO is an essential regulatory component of the IkappaB kinase (IKK) complex, which controls activation of the NF-kappaB signaling pathway. Herein, we show that NEMO exists as a disulfide-bonded dimer when isolated from several cell types and analyzed by SDS-polyacrylamide gel electrophoresis under non-reducing conditions. Treatment of cells with hydrogen peroxide (H(2)O(2)) induces further formation of NEMO dimers. Disulfide bond-mediated formation of NEMO dimers requires Cys54 and Cys347. The ability of these residues to form disulfide bonds is consistent with their location in a NEMO dimer structure that we generated by molecular modeling. We also show that pretreatment with H(2)O(2) decreases TNFalpha-induced IKK activity in NEMO-reconstituted cells, and that TNFalpha has a diminished ability to activate NF-kappaB DNA binding in cells reconstituted with NEMO mutant C54/347A. This study implicates NEMO as a target of redox regulation and presents the first structural model for the NEMO protein.

Pubmed ID: 18164680


  • Herscovitch M
  • Comb W
  • Ennis T
  • Coleman K
  • Yong S
  • Armstead B
  • Kalaitzidis D
  • Chandani S
  • Gilmore TD


Biochemical and biophysical research communications

Publication Data

February 29, 2008

Associated Grants

  • Agency: NCI NIH HHS, Id: CA47763
  • Agency: NIEHS NIH HHS, Id: ES03775
  • Agency: NCI NIH HHS, Id: R01 CA047763
  • Agency: NCI NIH HHS, Id: R01 CA047763-20

Mesh Terms

  • Animals
  • Base Sequence
  • Cell Nucleus
  • Cells, Cultured
  • Cysteine
  • DNA
  • Dimerization
  • Disulfides
  • Electrophoresis, Polyacrylamide Gel
  • Hydrogen Peroxide
  • I-kappa B Kinase
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Models, Molecular
  • Mutation
  • Oxidation-Reduction
  • Protein Binding
  • Tumor Necrosis Factor-alpha