Aberrantly increased hydrophobicity shared by mutants of Cu,Zn-superoxide dismutase in familial amyotrophic lateral sclerosis
Department of Neurology; Department of Molecular Genetics and Microbiology
Amyotrophic Lateral Sclerosis; Animals; Cell Line, Tumor; Dithiothreitol; Humans; Hydrophobicity; Mice; *Mutation; Superoxide Dismutase
Life Sciences | Medicine and Health Sciences
More than 100 different mutations in the gene encoding Cu,Zn-superoxide dismutase (SOD1) cause preferential motor neuron degeneration in familial amyotrophic lateral sclerosis (ALS). Although the cellular target(s) of mutant SOD1 toxicity have not been precisely specified, evidence to date supports the hypothesis that ALS-related mutations may increase the burden of partially unfolded SOD1 species. Influences that may destabilize SOD1 in vivo include impaired metal ion binding, reduction of the intrasubunit disulfide bond, or oxidative modification. In this study, we observed that metal-deficient as-isolated SOD1 mutants (H46R, G85R, D124V, D125H, and S134N) with disordered electrostatic and zinc-binding loops exhibited aberrant binding to hydrophobic beads in the absence of other destabilizing agents. Other purified ALS-related mutants that can biologically incorporate nearly normal amounts of stabilizing zinc ions (A4V, L38V, G41S, D90A, and G93A) exhibited maximal hydrophobic behavior after exposure to both a disulfide reducing agent and a metal chelator, while normal SOD1 was more resistant to these agents. Moreover, we detected hydrophobic SOD1 species in lysates from affected tissues in G85R and G93A mutant but not wildtype SOD1 transgenic mice. These findings suggest that a susceptibility to the cellular disulfide reducing environment and zinc loss may convert otherwise stable SOD1 mutants into metal-deficient forms with locally destabilized electrostatic and zinc-binding loops. These abnormally hydrophobic SOD1 species may promote aberrant interactions of the enzyme with itself or with other cellular constituents to produce toxicity in familial ALS.
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Citation: J Biol Chem. 2005 Aug 19;280(33):29771-9. Epub 2005 Jun 15. Link to article on publisher's site
The Journal of biological chemistry
Tiwari, Ashutosh; Xu, Zuoshang; and Hayward, Lawrence J., "Aberrantly increased hydrophobicity shared by mutants of Cu,Zn-superoxide dismutase in familial amyotrophic lateral sclerosis" (2005). Open Access Articles. 687.