title: Immature copper-zinc superoxide dismutase and familial amyotrophic lateral sclerosis.
abstract: Mutations in human copper-zinc superoxide dismutase (SOD1) cause an inherited form of amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease, motor neuron disease). Insoluble forms of mutant SOD1 accumulate in neural tissues of human ALS patients and in spinal cords of transgenic mice expressing these polypeptides, suggesting that SOD1-linked ALS is a protein misfolding disorder. Understanding the molecular basis for how the pathogenic mutations give rise to SOD1 folding intermediates, which may themselves be toxic, is therefore of keen interest. A critical step on the SOD1 folding pathway occurs when the copper chaperone for SOD1 (CCS) modifies the nascent SOD1 polypeptide by inserting the catalytic copper cofactor and oxidizing its intrasubunit disulfide bond. Recent studies reveal that pathogenic SOD1 proteins coming from cultured cells and from the spinal cords of transgenic mice tend to be metal-deficient and/or lacking the disulfide bond, raising the possibility that the disease-causing mutations may enhance levels of SOD1-folding intermediates by preventing or hindering CCS-mediated SOD1 maturation. This mini-review explores this hypothesis by highlighting the structural and biophysical properties of the pathogenic SOD1 mutants in the context of what is currently known about CCS structure and action. Other hypotheses as to the nature of toxicity inherent in pathogenic SOD1 proteins are not covered.
authors: Department of Biochemistry and the X-ray Crystallography Core Laboratory, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors: Sai V
authors: SV
authors: Seetharaman
authors: Mercedes
authors: M
authors: Prudencio
authors: Celeste
authors: C
authors: Karch
authors: Stephen P
authors: SP
authors: Holloway
authors: David R
authors: DR
authors: Borchelt
authors: P John
authors: PJ
authors: Hart
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D019281:Dimerization; D004195:Disease Models, Animal; D004220:Disulfides / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism; D009154:Mutation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D055672:Static Electricity; D013482:Superoxide Dismutase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D000682:Amyloid; D004220:Disulfides; D018832:Molecular Chaperones; D013482:Superoxide Dismutase