Novel mutations that enhance or repress the aggregation potential of SOD1.

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Krishnan U, Son M, Rajendran B, Elliott JL

Novel mutations that enhance or repress the aggregation potential of SOD1.

Mol Cell Biochem. 2006 Jul;287(1-2):201-11. Epub 2006 Apr 1.

PubMed ID

16583143 [ View in PubMed

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Abstract

Mutations in SOD1 cause FALS by a gain of function likely related to protein misfolding and aggregation. SOD1 mutations encompass virtually every domain of the molecule, making it difficult to identify motifs important in SOD1 aggregation. Zinc binding to SOD1 is important for structural integrity, and is hypothesized to play a role in mutant SOD1 aggregation. To address this question, we mutated the unique zinc binding sites of SOD1 and examined whether these changes would influence SOD1 aggregation. We generated single and multiple mutations in SOD1 zinc binding residues (H71, H80 and D83) either alone or in combination with an aggregate forming mutation (A4V) known to cause disease. These SOD1 mutants were assayed for their ability to form aggregates. Using an in vitro cellular SOD1 aggregation assay, we show that combining A4V with mutations in non-zinc binding domains (G37R or G85R) increases SOD1 aggregation potential. Mutations at two zinc binding residues (H71G and D83G) also increase SOD1 aggregation potential. However, an H80G mutation at the third zinc binding residue decreases SOD1 aggregation potential even in the context of other aggregate forming SOD1 mutations. These results demonstrate that various mutations have different effects on SOD1 aggregation potential and that the H80G mutation appears to uniquely act as a dominant inhibitor of SOD1 aggregation.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Zinc	Superoxide dismutase [Cu-Zn]	Protein	Humans	Unknown	Not Available	Details
Zinc acetate	Superoxide dismutase [Cu-Zn]	Protein	Humans	Unknown	Not Available	Details
Zinc chloride	Superoxide dismutase [Cu-Zn]	Protein	Humans	Unknown	Cofactor	Details
Zinc sulfate, unspecified form	Superoxide dismutase [Cu-Zn]	Protein	Humans	Unknown	Cofactor	Details