Metal Deficiency Increases Aberrant Hydrophobicity of Mutant Superoxide Dismutases That Cause Amyotrophic Lateral Sclerosis

• DOI: 10.1074/jbc.m109.043729
• Publication Date: 2009-08-04T00:59:32Z
• Authors: Ashutosh Tiwari; Amir Liba; Se Hui Sohn; Sai V. Seetharaman; Osman Bilsel; C.Robert Matthews; P.John Hart; Joan Selverstone ...; Lawrence J. Hayward
• Keywords: Dismutase

The mechanisms by which mutant variants of Cu/Zn-superoxide dismutase (SOD1) cause familial amyotrophic lateral sclerosis are not clearly understood. Evidence to date suggests that altered conformations SOD1s trigger perturbations cellular homeostasis ultimately motor neuron degeneration. In this study we correlated the metal contents and disulfide bond status purified wild-type (WT) SOD1 proteins changes in electrophoretic mobility surface hydrophobicity as detected 1-anilinonaphthalene-8-sulfonic acid (ANS) fluorescence. As-isolated WT were copper-deficient exhibited mobilities with their expected negative charge. However, upon reduction demetallation at physiological pH, both underwent a conformational change produced slower indicative partial unfolding. Furthermore, although ANS did bind appreciably holoenzyme, incubation metal-deficient or increased fluorescence shifted its peak toward shorter wavelengths. This interaction was greater for could be reversed addition ions, especially Cu(2+), even incapable forming bond. Overall, our findings support notion misfolding associated deficiency may facilitate aberrant interactions itself other constituents thereby contribute neuronal toxicity.