Modifications of superoxide dismutase (SOD1) in human erythrocytes: A possible role in amyotrophic lateral sclerosis

Kyle C. Wilcox, Li Zhou, Joshua K. Jordon, Yi Huang, Yanbao Yu, Rachel L. Redler, Xian Chen, Michael Caplow, Nikolay Dokholyan

Research output: Contribution to journalArticle

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Abstract

Over 100 mutations in Cu/Zn-superoxide dismutase (SOD1) result in familial amyotrophic lateral sclerosis. Dimer dissociation is the first step in SOD1 aggregation, and studies suggest nearly every amino acid residue in SOD1 is dynamically connected to the dimer interface. Post-translational modifications of SOD1 residues might be expected to have similar effects to mutations, but few modifications have been identified. Here we show, using SOD1 isolated from human erythrocytes, that human SOD1 is phosphorylated at threonine 2 and glutathionylated at cysteine 111. A second SOD1 phosphorylation was observed and mapped to either Thr-58 or Ser-59. Cysteine 111 glutathionylation promotes SOD1 monomer formation, a necessary initiating step in SOD1 aggregation, by causing a 2-fold increase in the Kd. This change in the dimer stability is expected to result in a 67% increase in monomer concentration, 315 nM rather than 212 nM at physiological SOD1 concentrations. Because protein glutathionylation is associated with redox regulation, our finding that glutathionylation promotes SOD1 monomer formation supports a model in which increased oxidative stress promotes SOD1 aggregation.

Original languageEnglish (US)
Pages (from-to)13940-13947
Number of pages8
JournalJournal of Biological Chemistry
Volume284
Issue number20
DOIs
StatePublished - May 15 2009

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Amyotrophic Lateral Sclerosis
Dimers
Superoxide Dismutase
Cysteine
Agglomeration
Monomers
Erythrocytes
Mutation
Threonine
Post Translational Protein Processing
Oxidation-Reduction
Phosphorylation
Oxidative Stress
Oxidative stress
Amino Acids
Proteins
Superoxide Dismutase-1
Amyotrophic lateral sclerosis 1

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Wilcox, Kyle C. ; Zhou, Li ; Jordon, Joshua K. ; Huang, Yi ; Yu, Yanbao ; Redler, Rachel L. ; Chen, Xian ; Caplow, Michael ; Dokholyan, Nikolay. / Modifications of superoxide dismutase (SOD1) in human erythrocytes : A possible role in amyotrophic lateral sclerosis. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 20. pp. 13940-13947.
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Modifications of superoxide dismutase (SOD1) in human erythrocytes : A possible role in amyotrophic lateral sclerosis. / Wilcox, Kyle C.; Zhou, Li; Jordon, Joshua K.; Huang, Yi; Yu, Yanbao; Redler, Rachel L.; Chen, Xian; Caplow, Michael; Dokholyan, Nikolay.

In: Journal of Biological Chemistry, Vol. 284, No. 20, 15.05.2009, p. 13940-13947.

Research output: Contribution to journalArticle

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