Abstract
Loss of stability of proteins is associated with their misfolding and aggregation which results in disease. Despite of the higher stability of Cu/Zn superoxide dismutase (SOD1), the point mutations destabilize its structure, results in oligomerization and the aggregation of SOD1 which is closely associated with the motor neuron disorder, amyotrophic lateral sclerosis. In the present study, we analyzed the role of two SOD1 mutants V14G and E100G which are located far away from the metal sites, dimer interface and disulfide region. The SOD1 mutants were recombinantly produced and their activity, structure and stability were investigated using biochemical methods, CD and DSC methods. In comparison with wild-type SOD1, the mutants exhibited reduced activity and the CD data showed comparable secondary structures composition. However, the stability studies using chemical and thermal denaturation methods showed the mutants are destabilized. Interestingly, our DSC data strongly suggested the destabilization of the mutants is due to the partial metalation of Cu/Zn ions. This observation emphasizes that although the mutations V14G and E100G are located away from the metal sites, they could affect the metal binding similar to metal binding region mutants, which are more susceptible to misfold and aggregate.
Published Version
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