title: Structures of the G85R variant of SOD1 in familial amyotrophic lateral sclerosis.
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 SOD1 induces 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.
authors: Department of Biochemistry and the X-ray Crystallography Core Laboratory, The University of Texas Health Ssience Center, San Antonio, Texas 78229, USA.
authors: Xiaohang
authors: X
authors: Cao
authors: Svetlana V
authors: SV
authors: Antonyuk
authors: Sai V
authors: SV
authors: Seetharaman
authors: Lisa J
authors: LJ
authors: Whitson
authors: Alexander B
authors: AB
authors: Taylor
authors: Stephen P
authors: SP
authors: Holloway
authors: Richard W
authors: RW
authors: Strange
authors: Peter A
authors: PA
authors: Doucette
authors: Joan Selverstone
authors: JS
authors: Valentine
authors: Ashutosh
authors: A
authors: Tiwari
authors: Lawrence J
authors: LJ
authors: Hayward
authors: Shelby
authors: S
authors: Padua
authors: Jeffrey A
authors: JA
authors: Cohlberg
authors: S Samar
authors: SS
authors: Hasnain
authors: P John
authors: PJ
authors: Hart
mesh_terms: D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000201:enzymology; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D011994:Recombinant Proteins; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1