title: Conversion of natively unstructured α-synuclein to its α-helical conformation significantly attenuates production of reactive oxygen species.
abstract: The intracellular α-synuclein (α-syn) protein, whose conformational change and aggregation have been closely linked to the pathology of Parkingson's disease (PD), is highly populated at the presynaptic termini and remains there in the α-helical conformation. In this study, circular dichroism confirmed that natively unstructured α-syn in aqueous solution was transformed to its α-helical conformation upon addition of trifluoroethanol (TFE). Electrochemical and UV-visible spectroscopic experiments reveal that both Cu (I) and Cu (II) are stabilized, with the former being stabilized by about two orders of magnitude. Compared to unstructured α-syn (Binolfi et al., J. Am. Chem. Soc. 133 (2011) 194-196), α-helical α-syn stabilizes Cu (I) by more than three orders of magnitude. Through the measurements of H(2)O(2) and hydroxyl radicals (OH) in solutions containing different forms of Cu (II) (free and complexed by unstructured or α-helical α-syn), we demonstrate that the significantly enhanced Cu (I) binding affinity helps inhibit the production of highly toxic reactive oxygen species, especially the hydroxyl radicals. Our study provides strong evidence that, as a possible means to prevent neuronal cell damage, conversion of the natively unstructured α-syn to its α-helical conformation in vivo could significantly attenuate the copper-modulated ROS production.
authors.affiliation: College of Chemistry and Chemical Engineering, Central South University, Changsha, Hunan 410083, PR China.
authors.forename: Binbin
authors.initials: B
authors.lastname: Zhou
authors.forename: Yuanqiang
authors.initials: Y
authors.lastname: Hao
authors.forename: Chengshan
authors.initials: C
authors.lastname: Wang
authors.forename: Ding
authors.initials: D
authors.lastname: Li
authors.forename: You-Nian
authors.initials: YN
authors.lastname: Liu
authors.forename: Feimeng
authors.initials: F
authors.lastname: Zhou
mesh_terms: D000595:Amino Acid Sequence; D003300:Copper / Q000737:chemistry; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry*; D006878:Hydroxides / Q000737:chemistry*; D007700:Kinetics; D008969:Molecular Sequence Data; D011485:Protein Binding; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017382:Reactive Oxygen Species / Q000737:chemistry; D012997:Solvents / Q000737:chemistry; D014270:Trifluoroethanol / Q000737:chemistry; D014867:Water / Q000737:chemistry; D051844:alpha-Synuclein / Q000737:chemistry*
chemical_list: D006878:Hydroxides; D017382:Reactive Oxygen Species; D012997:Solvents; D051844:alpha-Synuclein; D014867:Water; D014270:Trifluoroethanol; D003300:Copper; C031356:hydroxide ion; D006861:Hydrogen Peroxide