A Common Property of Amyotrophic Lateral Sclerosis-associated Variants: DESTABILIZATION OF THE COPPER/ZINC SUPEROXIDE DISMUTASE ELECTROSTATIC LOOP*

AUTOR(ES)

Molnar, Kathleen S.

FONTE

American Society for Biochemistry and Molecular Biology

RESUMO

At least 119 mutations in the gene encoding copper/zinc superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis by an unidentified toxic gain of function. We compared the dynamic properties of 13 as-isolated, partially metallated, SOD1 variant enzymes using hydrogen-deuterium exchange. We identified a shared property of these familial amyotrophic lateral sclerosis-related SOD1 variants, namely structural and dynamic change affecting the electrostatic loop (loop VII) of SOD1. Furthermore, SOD1 variants that have severely compromised metal binding affinities demonstrated additional structural and dynamic changes to the zinc-binding loop (loop IV) of SOD1. Although the biological consequences of increased loop VII mobility are not fully understood, this common property is consistent with the hypotheses that SOD1 mutations exert toxicity via aggregation or aberrant association with other cellular constituents.

Documentos Relacionados

• Caspase-1 is activated in neural cells and tissue with amyotrophic lateral sclerosis-associated mutations in copper-zinc superoxide dismutase
• Structural Changes to Monomeric CuZn Superoxide Dismutase Caused by the Familial Amyotrophic Lateral Sclerosis-Associated Mutation A4V
• Characterization of three yeast copper-zinc superoxide dismutase mutants analogous to those coded for in familial amyotrophic lateral sclerosis.
• Mutations in copper-zinc superoxide dismutase that cause amyotrophic lateral sclerosis alter the zinc binding site and the redox behavior of the protein.
• Transgenic copper/zinc superoxide dismutase modulates susceptibility to type I diabetes.