Disulfide Scrambling Describes the Oligomer Formation of Superoxide Dismutase (SOD1) Proteins in the Familial Form of Amyotrophic Lateral Sclerosis*

Background: Cu,Zn-superoxide dismutase (SOD1) possesses a highly conserved intramolecular disulfide bond. Results: Structural destabilization of SOD1 scrambles the intramolecular disulfide to form cross-linked oligomers with an intermolecular disulfide bond. Conclusion: Disulfide scrambling is a key to understand the folding/misfolding process of SOD1. Significance: A disulfide-scrambling model provides a molecular pathomechanism describing the formation of disulfide-linked SOD1 oligomers in amyotrophic lateral sclerosis. Dominant mutations in Cu,Zn-superoxide dismutase (SOD1) are a cause of a familial form of amyotrophic lateral sclerosis. Wild-type SOD1 forms a highly conserved intra-molecular disulfide bond, whereas pathological SOD1 proteins are cross-linked via intermolecular disulfide bonds and form insoluble oligomers. A thiol-disulfide status in SOD1 will thus play a regulatory role in determining its folding/misfolding pathways; however, it remains unknown how pathogenic mutations in SOD1 affect the thiol-disulfide status to facilitate the protein misfolding. Here, we show that the structural destabilization of SOD1 scrambles a disulfide bond among four Cys residues in an SOD1 molecule. The disulfide scrambling produces SOD1 monomers with distinct electrophoretic mobility and also reproduces the formation of disulfide-linked oligomers. We have also found that the familial form of amyotrophic lateral sclerosis-causing mutations facilitate the disulfide scrambling in SOD1. Based upon our results, therefore, scrambling of the conserved disulfide bond will be a key event to cause the pathological changes in disease-associated mutant SOD1 proteins.

• Publication year

  2012

• Venue

  Journal of Biological Chemistry

• Publication date

  2012-12-21

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1074/jbc.M112.414235PMID 23264618PMCID PMC3576100
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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