title: Conformational Disorder of the Most Immature Cu, Zn-Superoxide Dismutase Leading to Amyotrophic Lateral Sclerosis.
abstract: Misfolding of Cu,Zn-superoxide dismutase (SOD1) is a pathological change in the familial form of amyotrophic lateral sclerosis caused by mutations in the SOD1 gene. SOD1 is an enzyme that matures through the binding of copper and zinc ions and the formation of an intramolecular disulfide bond. Pathogenic mutations are proposed to retard the post-translational maturation, decrease the structural stability, and hence trigger the misfolding of SOD1 proteins. Despite this, a misfolded and potentially pathogenic conformation of immature SOD1 remains obscure. Here, we show significant and distinct conformational changes of apoSOD1 that occur only upon reduction of the intramolecular disulfide bond in solution. In particular, loop regions in SOD1 lose their restraint and become significantly disordered upon dissociation of metal ions and reduction of the disulfide bond. Such drastic changes in the solution structure of SOD1 may trigger misfolding and fibrillar aggregation observed as pathological changes in the familial form of amyotrophic lateral sclerosis.
authors.affiliation: From the Laboratory for Mechanistic Chemistry of Biomolecules, Department of Chemistry, Keio University, Yokohama 223-8522, furukawa@chem.keio.ac.jp.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Furukawa
authors.affiliation: From the Laboratory for Mechanistic Chemistry of Biomolecules, Department of Chemistry, Keio University, Yokohama 223-8522.
authors.forename: Itsuki
authors.initials: I
authors.lastname: Anzai
authors.affiliation: Research Center of Integrative Molecular Systems (CIMoS), Institute for Molecular Science, Okazaki 444-8585, Department of Functional Molecular Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki 444-8585.
authors.forename: Shuji
authors.initials: S
authors.lastname: Akiyama
authors.affiliation: Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo 060-8628, and.
authors.forename: Mizue
authors.initials: M
authors.lastname: Imai
authors.affiliation: Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo 060-8628, and.
authors.forename: Fatima Joy C
authors.initials: FJ
authors.lastname: Cruz
authors.affiliation: Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo 060-8628, and Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan.
authors.forename: Tomohide
authors.initials: T
authors.lastname: Saio
authors.affiliation: From the Laboratory for Mechanistic Chemistry of Biomolecules, Department of Chemistry, Keio University, Yokohama 223-8522.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Nagasawa
authors.affiliation: From the Laboratory for Mechanistic Chemistry of Biomolecules, Department of Chemistry, Keio University, Yokohama 223-8522.
authors.forename: Takao
authors.initials: T
authors.lastname: Nomura
authors.affiliation: Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo 060-8628, and Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Ishimori
mesh_terms: D000690:Amyotrophic Lateral Sclerosis; D003300:Copper / Q000737:chemistry* / Q000378:metabolism; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D066263:Protein Aggregation, Pathological; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013482:Superoxide Dismutase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D015032:Zinc / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004220:Disulfides; C000606290:SOD1 protein, human; D003300:Copper; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D015032:Zinc
keywords: amyotrophic lateral sclerosis (ALS) (Lou Gehrig disease); protein aggregation; protein folding; protein misfolding; superoxide dismutase (SOD)