Conformational disorder of the most immature Cu, Zn-superoxide dismutase leading to amyotrophic lateral sclerosis

Yoshiaki Furukawa, Itsuki Anzai, Shuji Akiyama, Mizue Imai, Fatima Joy C Cruz, Tomohide Saio, Kenichi Nagasawa, Takao Nomura, Koichiro Ishimori

Research output: Contribution to journalArticle

17 Citations (Scopus)

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 bondinsolution. Inparticular, 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.

Original languageEnglish
Pages (from-to)4144-4155
Number of pages12
JournalJournal of Biological Chemistry
Volume291
Issue number8
DOIs
Publication statusPublished - 2016 Feb 19

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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    Furukawa, Y., Anzai, I., Akiyama, S., Imai, M., Cruz, F. J. C., Saio, T., Nagasawa, K., Nomura, T., & Ishimori, K. (2016). Conformational disorder of the most immature Cu, Zn-superoxide dismutase leading to amyotrophic lateral sclerosis. Journal of Biological Chemistry, 291(8), 4144-4155. https://doi.org/10.1074/jbc.M115.683763