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

被引：83

作者：

Cao, Xiaohang ^{[1
,2
]}

Antonyuk, Svetlana V. ^{[4
]}

Seetharaman, Sai V. ^{[1
,2
]}

Whitson, Lisa J. ^{[1
,2
]}

Taylor, Alexander B. ^{[1
,2
]}

Holloway, Stephen P. ^{[1
,2
]}

Strange, Richard W. ^{[4
]}

Doucette, Peter A. ^{[5
]}

Valentine, Joan Selverstone ^{[5
]}

Tiwari, Ashutosh ^{[6
]}

Hayward, Lawrence J. ^{[6
]}

Padua, Shelby ^{[7
]}

Cohlberg, Jeffrey A. ^{[7
]}

Hasnain, S. Samar ^{[4
]}

Hart, P. John ^{[1
,2
,3
]}

机构：

[1] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA

[2] Univ Texas Hlth Sci Ctr San Antonio, Xray Crystallog Core Lab, San Antonio, TX 78229 USA

[3] Univ Texas Hlth Sci Ctr San Antonio, Ctr Geriatr Res Educ & Clin, Dept Vet Affairs, San Antonio, TX 78229 USA

[4] SERC, Daresbury Lab, Mol Biophys Grp, Sci & Technol Facil Council, Warrington WA4 4AD, Cheshire, England

[5] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA

[6] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA 01655 USA

[7] Calif State Univ Long Beach, Dept Chem & Biochem, Long Beach, CA 90840 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2008年 / 283卷 / 23期

关键词：

D O I：

10.1074/jbc.M801522200

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：16169 / 16177

页数：9

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