N-terminal acetylation of superoxide dismutase 1 accelerates amyloid formation without general destabilization of the apo-state

Co- and posttranslational modifications can significantly impact the structure, dynamics and function of proteins. In this study we investigate how N-terminal acetylation affects misfolding and self-assembly of the enzyme superoxide dismutase 1 (SOD1), implicated in amyotrophic lateral sclerosis (ALS). Studies of protein inclusions in patient samples and animal models have shown that wild-type SOD1 can form amyloid fibrils even when no mutations are found in the sod1 -gene. This has identified SOD1 amyloid formation as a possible common denominator of ALS and may suggest that co- and posttranslational modifications, like N-terminal acetylation found in human SOD1, can be a factor in disease development. In this work the impact of N-terminal acetylation of SOD1 on stability and aggregation is characterized. Results show that the structure and thermal stability of the apo-state are unaffected by the modification while the amyloid formation rate is significantly enhanced. This is caused by a shortening of the nucleation phase together with an increase of fibril elongation by more than 10-fold upon N-terminal acetylation of SOD1. Collectively the findings demonstrate how regulation by co- and posttranslational modifications can influence protein misfolding and self-assembly.