title: 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.
abstract: Substantial evidence implicates that the aggregation of α-synuclein (αSyn) is a critical factor in the pathogenesis of Parkinson's disease. This study focuses on the role of αSyn 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 α-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 α-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 αSyn and thus prevent αSyn from changing conformation, which is a critical step for fibrillation.
authors.affiliation: Research Center for Protein Chemistry, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX 77030, USA.
authors.forename: Dong-Pyo
authors.initials: DP
authors.lastname: Hong
authors.forename: Wei
authors.initials: W
authors.lastname: Xiong
authors.forename: Jui-Yoa
authors.initials: JY
authors.lastname: Chang
authors.forename: Chuantao
authors.initials: C
authors.lastname: Jiang
mesh_terms: D052160:Benzothiazoles; D002942:Circular Dichroism; D003545:Cysteine / Q000737:chemistry; D003553:Cystine / Q000737:chemistry*; D005456:Fluorescent Dyes / Q000737:chemistry; D006801:Humans; D007536:Isomerism; D007700:Kinetics; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000737:chemistry; D010084:Oxidation-Reduction; D010300:Parkinson Disease / Q000503:physiopathology; D011489:Protein Denaturation; D017510:Protein Folding; D055550:Protein Stability; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry; D013050:Spectrometry, Fluorescence; D013844:Thiazoles / Q000737:chemistry; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics
chemical_list: D052160:Benzothiazoles; D005456:Fluorescent Dyes; D050505:Mutant Proteins; D011994:Recombinant Proteins; C497604:SNCA protein, human; D013844:Thiazoles; D051844:alpha-Synuclein; C009462:thioflavin T; D003553:Cystine; D003545:Cysteine