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J. Biol. Chem., Vol. 283, Issue 23, 16169-16177, June 6, 2008

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Structures of the G85R Variant of SOD1 in Familial Amyotrophic Lateral Sclerosis^*

Xiaohang Cao¹, Svetlana V. Antonyuk¹, Sai V. Seetharaman, Lisa J. Whitson², 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^**3, S. Samar Hasnain, and P. John Hart⁴

From the Department of Biochemistry and the X-ray Crystallography Core Laboratory and the Geriatric Research, Education, and Clinical Center, Department of Veterans Affairs, South Texas Veterans Health Care System, The University of Texas Health Science Center, San Antonio, Texas 78229, Molecular Biophysics Group, Science and Technology Facilities Council, Daresbury Laboratory, Warrington, Cheshire WA44AD, United Kingdom, ^¶Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, ^||Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, and ^**Department of Chemistry and Biochemistry, California State University, Long Beach, California 90840

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.

Received for publication, February 25, 2008

The atomic coordinates and structure factors (codes 3CQP, 3CQQ, 2VR6, 2VR7, and 2VR8) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported, in whole or in part, by National Institutes of Health Grants NS39112 (to P. J. H.), NS44170 (to L. J. H.), and NS049134 (to J. S. V.) from the NINDS and Grant GM28222 (to J. S. V.) from the NIGMS. This work was also supported by the Judith and Jean Pape Adams Charitable Foundation (to P. J. H.), the Motor Neuron Disease Association (to S. S. H.), and the ALS Association (to L. J. H., J. A. C., and J. S. V.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1.

¹ Both authors contributed equally to this work.

² Supported by a Ford Foundation predoctoral fellowship for minorities and by a grant from the American Foundation for Aging Research.

³ Additionally supported by Research Corp. Grant CC5571 and by a grant from California State University, Long Beach.

⁴ To whom correspondence should be addressed. Tel.: 210-567-0751; Fax: 210-567-6595; E-mail: pjhart{at}biochem.uthscsa.edu.

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