The role of the C-terminus of human α-synuclein: Intra-disulfide bonds between the C-terminus and other regions stabilize non-fibrillar monomeric isomers

Substantial evidence implicates that the aggregation of alpha-synuclein (alpha Syn) is a critical factor in the pathogenesis of Parkinson's disease. This study focuses on the role of alpha Syn C-terminus. We introduced two additional cysteine residues at positions 107 and 124 (A107C and A124C) to our previous construct. Five X-isomers of oxidative-folded mutation of alpha-synuclein with three disulfides were isolated and their secondary structures and aggregating features were analyzed. All isomers showed similar random coil structures as wild-type alpha-synuclein. However, these isomers did not form aggregates or fibrils, even with prolonged incubation, suggesting that the interactions between the C-terminal and N-terminal or central NAC region are important in maintaining the natively unfolded structure of alpha Syn and thus prevent alpha Syn from changing conformation, which is a critical step for fibrillation. Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies.