title: Structural basis of Cu, Zn-superoxide dismutase amyloid fibril formation involves interaction of multiple peptide core regions.
abstract: Cu, Zn-superoxide dismutase (SOD1), an enzyme implicated in the progression of familial amyotrophic lateral sclerosis (fALS), forms amyloid fibrils under certain experimental conditions. As part of our efforts to understand ALS pathogenesis, in this study we found that reduction of the intramolecular disulfide bond destabilized the tertiary structure of metal free wild-type SOD1 and greatly enhanced fibril formation in vitro. We also identified fibril core peptides that are resistant to protease digestion by using mass spectroscopy and Edman degradation analyses. Three regions dispersed throughout the sequence were detected as fibril core sequences of SOD1. Interestingly, by using three synthetic peptides that correspond to these identified regions, we determined that each region was capable of fibril formation, either alone or in a mixture containing multiple peptides. It was also revealed that by reducing the disulfide bond and causing a decrease in the structural stability, the amyloid fibril formation of a familial mutant SOD1 G93A was accelerated even under physiological conditions. These results demonstrate that by destabilizing the structure of SOD1 by removing metal ions and breaking the intramolecular disulfide bridge, multiple fibril-forming core regions are exposed, which then interact with each another and form amyloid fibrils under physiological conditions.
authors: Department of Chemistry and Biotechnology, Graduate School of Engineering.
authors: Masataka
authors: M
authors: Ida
authors: Department of Chemistry and Biotechnology, Graduate School of Engineering.
authors: Mizuho
authors: M
authors: Ando
authors: Department of Chemistry and Biotechnology, Graduate School of Engineering.
authors: Masayuki
authors: M
authors: Adachi
authors: Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science and.
authors: Asumi
authors: A
authors: Tanaka
authors: Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science and.
authors: Kodai
authors: K
authors: Machida
authors: Department of Chemistry and Biotechnology, Graduate School of Engineering, Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science and.
authors: Kunihiro
authors: K
authors: Hongo
authors: Department of Chemistry and Biotechnology, Graduate School of Engineering, Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science and.
authors: Tomohiro
authors: T
authors: Mizobata
authors: Division of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Tottori, Japan.
authors: Miho Yoshida
authors: MY
authors: Yamakawa
authors: Division of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Tottori, Japan.
authors: Yasuhiro
authors: Y
authors: Watanabe
authors: Division of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Tottori, Japan.
authors: Kenji
authors: K
authors: Nakashima
authors: Department of Chemistry and Biotechnology, Graduate School of Engineering, Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science and kawata@bio.tottori-u.ac.jp.
authors: Yasushi
authors: Y
authors: Kawata
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry*; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D009154:Mutation; D010084:Oxidation-Reduction; D010455:Peptides / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D013482:Superoxide Dismutase / Q000737:chemistry* / Q000235:genetics; D000072105:Superoxide Dismutase-1
chemical_list: D000682:Amyloid; D010455:Peptides; C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: ALS; SOD1G93A mutant; amyloid fibril core; mechanism; structural stability