α-Synuclein Conformation Affects Its Tyrosine-Dependent Oxidative Aggregation

• Published in: Biochemistry (Easton) Vol. 47; no. 51; pp. 13604 - 13609
• Main Authors: Ruf, Rebecca A. S, Lutz, Evan A, Zigoneanu, Imola G, Pielak, Gary J
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 23.12.2008
• Subjects: alpha-Synuclein - chemistry; Cytochromes c - chemistry; Humans; Hydrogen Peroxide - chemistry; Molecular Conformation; Mutation; Oxidative Stress; Oxygen - chemistry; Parkinson Disease - metabolism; Protein Binding; Protein Denaturation; Protein Structure, Tertiary; Recombinant Proteins - chemistry; Tyrosine - chemistry
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi801884z

Oxidative stress and aggregation of the protein α-synuclein are thought to be key factors in Parkinson’s disease. Previous work shows that cytochrome c with H2O2 causes tyrosine-dependent in vitro peroxidative aggregation of proteins, including α-synuclein. Here, we examine the role of each of α-synuclein’s four tyrosine residues and how the protein’s conformation affects covalent oxidative aggregation. When α-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 α-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.