title: Alpha-Synuclein conformation affects its tyrosine-dependent oxidative aggregation.
abstract: Oxidative stress and aggregation of the protein alpha-synuclein are thought to be key factors in Parkinson's disease. Previous work shows that cytochrome c with H(2)O(2) causes tyrosine-dependent in vitro peroxidative aggregation of proteins, including alpha-synuclein. Here, we examine the role of each of alpha-synuclein's four tyrosine residues and how the protein's conformation affects covalent oxidative aggregation. When alpha-synuclein adopts a collapsed conformation, tyrosine 39 is essential for wild-type-like covalent aggregation. This lone N-terminal tyrosine, however, is not required for wild-type-like covalent aggregation in the presence of a denaturant or when alpha-synuclein is present in noncovalent fibrils. We also show that preformed oxidative aggregates are not incorporated into noncovalent fibrils. These data provide insight into how dityrosine may be formed in Lewy bodies seen in Parkinson's disease.
authors.affiliation: Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Rebecca A S
authors.initials: RA
authors.lastname: Ruf
authors.forename: Evan A
authors.initials: EA
authors.lastname: Lutz
authors.forename: Imola G
authors.initials: IG
authors.lastname: Zigoneanu
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Pielak
mesh_terms: D045304:Cytochromes c / Q000737:chemistry; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D008968:Molecular Conformation; D009154:Mutation; D018384:Oxidative Stress; D010100:Oxygen / Q000737:chemistry*; D010300:Parkinson Disease / Q000378:metabolism; D011485:Protein Binding; D011489:Protein Denaturation; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry; D014443:Tyrosine / Q000737:chemistry*; D051844:alpha-Synuclein / Q000737:chemistry*
chemical_list: D011994:Recombinant Proteins; D051844:alpha-Synuclein; D014443:Tyrosine; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D010100:Oxygen