title: Disulfide scrambling describes the oligomer formation of superoxide dismutase (SOD1) proteins in the familial form of amyotrophic lateral sclerosis.
abstract: 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.
authors.affiliation: Laboratory for Mechanistic Chemistry of Biomolecules, Department of Chemistry, Keio University, Yokohama, Kanagawa 223-8522, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Toichi
authors.forename: Koji
authors.initials: K
authors.lastname: Yamanaka
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Furukawa
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D003545:Cysteine / Q000737:chemistry; D004220:Disulfides / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006801:Humans; D007700:Kinetics; D013058:Mass Spectrometry / Q000379:methods; D008954:Models, Biological; D009154:Mutation; D011489:Protein Denaturation; D017510:Protein Folding; D013438:Sulfhydryl Compounds / Q000737:chemistry; D013482:Superoxide Dismutase / Q000378:metabolism*; D013696:Temperature; D013997:Time Factors
chemical_list: D003432:Cross-Linking Reagents; D004220:Disulfides; D013438:Sulfhydryl Compounds; D013482:Superoxide Dismutase; D003545:Cysteine