Copper–Zinc Superoxide Dismutase, Its Copper Chaperone, and Familial Amyotrophic Lateral Sclerosis

Winkler, Duane D.; Prudencio, Mercedes; Karch, Celeste M.; Borchelt, David R.; Hart, P. John

doi:10.1002/9780470572702.ch17

Cited by 5 publications

(9 citation statements)

References 138 publications

(59 reference statements)

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“…Recent work by Nordlund, Oliveberg, and colleagues is particularly notable because the non-native SOD1-SOD1 interactions highlighted in Figure 2A were also observed in the structure an SOD1 protein engineered to be exclusively monomeric, which led them to suggest that the interactions at this interface may initiate aggregation of pathogenic SOD1 proteins in vivo (42, 43). In each of these cases, the absence of metal ions in the zinc-binding site appears to be necessary for these non-native intermolecular SOD1 interactions to occur, consistent with the notion that immature SOD1 proteins may represent the noxious entities in SOD1-linked ALS (4, 5, 19). …”

Section: Discussionsupporting

confidence: 74%

“…In the early 1990s, mutations in the human gene encoding SOD1 were linked to the fatal, progressive neurodegenerative disease amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease) (2, 3). Today, more than 100 distinct pathogenic mutations have been documented (reviewed in refs (4) and (5)), with most resulting in single amino acid substitutions and a few in truncations of the polypeptide.…”

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confidence: 99%

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Disrupted Zinc-Binding Sites in Structures of Pathogenic SOD1 Variants D124V and H80R

Seetharaman¹,

Winkler²,

Taylor³

et al. 2010

Biochemistry

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Mutations in human copper-zinc superoxide dismutase (SOD1) cause an inherited form of the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS). Here, we present structures of the pathogenic SOD1 variants D124V and H80R, both of which demonstrate compromised zinc-binding sites. The disruption of the zinc-binding sites in H80R SOD1 leads to conformational changes in loop elements, permitting non-native SOD1-SOD1 interactions that mediate the assembly of these proteins into higher order filamentous arrays. Analytical ultracentrifugation sedimentation velocity experiments indicate that these SOD1 variants are more prone to monomerization than is the wild type enzyme. Although D124V and H80R SOD1 proteins appear to have fully functional copper-binding sites, inductively coupled plasma mass spectrometery (ICP-MS) and anomalous scattering X-ray diffraction analyses reveal that zinc (not copper) occupies the copper-binding sites in these variants. The absence of copper in these proteins, together with the results of covalent thiol modification experiments in yeast strains with and without the gene encoding the copper chaperone for SOD1 (CCS), suggest that CCS may not fully act on newly translated forms of these polypeptides. Overall, these findings lend support to the hypothesis that immature mutant SOD1 species contribute to toxicity in SOD1-linked ALS.

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Section: Discussionsupporting

confidence: 74%

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confidence: 99%

Disrupted Zinc-Binding Sites in Structures of Pathogenic SOD1 Variants D124V and H80R

Seetharaman¹,

Winkler²,

Taylor³

et al. 2010

Biochemistry

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“…A key observation in assessing these divergent potential mechanisms of mutant SOD1 aggregation is that regardless of the location of the mutation, the protein that appears to comprise such aggregates lack critical post-translational modifications, including incorporation of Cu and formation of intramolecular disulfide bonds (Jonsson et al 2006a; Karch et al 2009; Lelie et al 2011). Given the importance of post-translational modification in the stability of SOD1, there could be examples of mutations that have little impact on SOD1 structurally and instead alter some key interactions with the copper chaperone for SOD1, leaving the protein deficient in Cu, less mature, and vulnerable to misfolding (Winkler et al 2010).…”

Section: Discussionmentioning

confidence: 99%

Experimental Mutations in Superoxide Dismutase 1 Provide Insight into Potential Mechanisms Involved in Aberrant Aggregation in Familial Amyotrophic Lateral Sclerosis

Crown

Roberts

Crosby

et al. 2019

G3 Genes|Genomes|Genetics

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Mutations in more than 80 different positions in superoxide dismutase 1 (SOD1) have been associated with amyotrophic lateral sclerosis (fALS). There is substantial evidence that a common consequence of these mutations is to induce the protein to misfold and aggregate. How these mutations perturb native structure to heighten the propensity to misfold and aggregate is unclear. In the present study, we have mutagenized Glu residues at positions 40 and 133 that are involved in stabilizing the β-barrel structure of the native protein and a critical Zn binding domain, respectively, to examine how specific mutations may cause SOD1 misfolding and aggregation. Mutations associated with ALS as well as experimental mutations were introduced into these positions. We used an assay in which mutant SOD1 was fused to yellow fluorescent protein (SOD1:YFP) to visualize the formation of cytosolic inclusions by mutant SOD1. We then used existing structural data on SOD1, to predict how different mutations might alter local 3D conformation. Our findings reveal an association between mutant SOD1 aggregation and amino acid substitutions that are predicted to introduce steric strain, sometimes subtly, in the 3D conformation of the peptide backbone.

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“…In addition, because sALS and fALS are similar clinically, it is possible that the underlying molecular causes for the two forms of the disease could be related and therapeutics effective for SOD1-linked ALS might prove effective for the more prevalent sporadic forms of the disease. Today, nearly 16 years after lesions in the gene encoding SOD1 were first linked to fALS, the number of distinct ALS-SOD1 mutations published in the literature has risen to ~100 (Table 1) (7, 8). However, an effective treatment has still not yet been identified and acquiring an understanding of the molecular basis for SOD1-linked ALS has proven elusive.…”

Section: Sod1 and Familial Alsmentioning

confidence: 99%

Immature Copper-Zinc Superoxide Dismutase and Familial Amyotrophic Lateral Sclerosis

Seetharaman

Prudencio

Karch

et al. 2009

Exp Biol Med (Maywood)

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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.

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Copper–Zinc Superoxide Dismutase, Its Copper Chaperone, and Familial Amyotrophic Lateral Sclerosis

Cited by 5 publications

References 138 publications

Disrupted Zinc-Binding Sites in Structures of Pathogenic SOD1 Variants D124V and H80R

Disrupted Zinc-Binding Sites in Structures of Pathogenic SOD1 Variants D124V and H80R

Experimental Mutations in Superoxide Dismutase 1 Provide Insight into Potential Mechanisms Involved in Aberrant Aggregation in Familial Amyotrophic Lateral Sclerosis

Immature Copper-Zinc Superoxide Dismutase and Familial Amyotrophic Lateral Sclerosis

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