Modifications of superoxide dismutase (SOD1) in human erythrocytes: a possible role in amyotrophic lateral sclerosis.
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 K(d). 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.
Wilcox
Kyle C
KC
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27510; Program in Molecular and Cellular Biophysics University of North Carolina, Chapel Hill, North Carolina 27510.
Zhou
Li
L
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27510; University of North Carolina-Duke Michael Hooker Proteomics Center University of North Carolina, Chapel Hill, North Carolina 27510.
Jordon
Joshua K
JK
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27510.
Huang
Yi
Y
Department of Chemistry and Institutes of Biomedical Sciences, Fudan University, Shanghai, China 200433.
Yu
Yanbao
Y
Department of Chemistry and Institutes of Biomedical Sciences, Fudan University, Shanghai, China 200433.
Redler
Rachel L
RL
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27510.
Chen
Xian
X
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27510; Program in Molecular and Cellular Biophysics University of North Carolina, Chapel Hill, North Carolina 27510; University of North Carolina-Duke Michael Hooker Proteomics Center University of North Carolina, Chapel Hill, North Carolina 27510. Electronic address: xian_chen@med.unc.edu.
Caplow
Michael
M
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27510.
Dokholyan
Nikolay V
NV
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27510; Program in Molecular and Cellular Biophysics University of North Carolina, Chapel Hill, North Carolina 27510; University of North Carolina Neuroscience Center, University of North Carolina, Chapel Hill, North Carolina 27510. Electronic address: dokh@med.unc.edu.
D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics; D019281:Dimerization; D004912:Erythrocytes / Q000201:enzymology*; D005978:Glutathione / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D018384:Oxidative Stress; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D005978:Glutathione