Structures of the G85R variant of SOD1 in familial amyotrophic lateral sclerosis

Xiaohang Cao, Svetlana V. Antonyuk, Sai V. Seetharaman, Lisa J. Whitson, Alexander B. Taylor, Stephen P. Holloway, Richard W. Strange, Peter A. Doucette, Joan Selverstone Valentine, Ashutosh Tiwari, Lawrence J. Hayward, Shelby Padua, Jeffrey A. Cohlberg, S. Samar Hasnain, P. John Hart

Research output: Contribution to journalArticle

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Abstract

Mutations in the gene encoding human copper-zinc superoxide dismutase (SOD1) cause a dominant form of the progressive neurodegenerative disease amyotrophic lateral sclerosis. Transgenic mice expressing the human G85R SOD1 variant develop paralytic symptoms concomitant with the appearance of SOD1-enriched proteinaceous inclusions in their neural tissues. The process(es) through which misfolding or aggregation of G85R SOD1induces motor neuron toxicity is not understood. Here we present structures of the human G85R SOD1 variant determined by single crystal x-ray diffraction. Alterations in structure of the metal-binding loop elements relative to the wild type enzyme suggest a molecular basis for the metal ion deficiency of the G85R SOD1 protein observed in the central nervous system of transgenic mice and in purified recombinant G85R SOD1. These findings support the notion that metal-deficient and/or disulfide-reduced mutant SOD1 species contribute to toxicity in SOD1-linked amyotrophic lateral sclerosis.

Original languageEnglish (US)
Pages (from-to)16169-16177
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number23
DOIs
StatePublished - Jun 6 2008

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Toxicity
Metals
Amyotrophic Lateral Sclerosis
Neurodegenerative diseases
Transgenic Mice
Gene encoding
Neurology
Disulfides
Neurons
Superoxide Dismutase
Metal ions
Zinc
Copper
Agglomeration
Diffraction
Single crystals
Motor Neurons
Tissue
X rays
Neurodegenerative Diseases

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Cao, X., Antonyuk, S. V., Seetharaman, S. V., Whitson, L. J., Taylor, A. B., Holloway, S. P., ... Hart, P. J. (2008). Structures of the G85R variant of SOD1 in familial amyotrophic lateral sclerosis. Journal of Biological Chemistry, 283(23), 16169-16177. https://doi.org/10.1074/jbc.M801522200

Structures of the G85R variant of SOD1 in familial amyotrophic lateral sclerosis. / Cao, Xiaohang; Antonyuk, Svetlana V.; Seetharaman, Sai V.; Whitson, Lisa J.; Taylor, Alexander B.; Holloway, Stephen P.; Strange, Richard W.; Doucette, Peter A.; Valentine, Joan Selverstone; Tiwari, Ashutosh; Hayward, Lawrence J.; Padua, Shelby; Cohlberg, Jeffrey A.; Hasnain, S. Samar; Hart, P. John.

In: Journal of Biological Chemistry, Vol. 283, No. 23, 06.06.2008, p. 16169-16177.

Research output: Contribution to journalArticle

Cao, X, Antonyuk, SV, Seetharaman, SV, Whitson, LJ, Taylor, AB, Holloway, SP, Strange, RW, Doucette, PA, Valentine, JS, Tiwari, A, Hayward, LJ, Padua, S, Cohlberg, JA, Hasnain, SS & Hart, PJ 2008, 'Structures of the G85R variant of SOD1 in familial amyotrophic lateral sclerosis', Journal of Biological Chemistry, vol. 283, no. 23, pp. 16169-16177. https://doi.org/10.1074/jbc.M801522200
Cao X, Antonyuk SV, Seetharaman SV, Whitson LJ, Taylor AB, Holloway SP et al. Structures of the G85R variant of SOD1 in familial amyotrophic lateral sclerosis. Journal of Biological Chemistry. 2008 Jun 6;283(23):16169-16177. https://doi.org/10.1074/jbc.M801522200
Cao, Xiaohang ; Antonyuk, Svetlana V. ; Seetharaman, Sai V. ; Whitson, Lisa J. ; Taylor, Alexander B. ; Holloway, Stephen P. ; Strange, Richard W. ; Doucette, Peter A. ; Valentine, Joan Selverstone ; Tiwari, Ashutosh ; Hayward, Lawrence J. ; Padua, Shelby ; Cohlberg, Jeffrey A. ; Hasnain, S. Samar ; Hart, P. John. / Structures of the G85R variant of SOD1 in familial amyotrophic lateral sclerosis. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 23. pp. 16169-16177.
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