Fibrils Of Alpha-Synuclein Abolish The Affinity Of Cu2+-Binding Site To His50 And Induce Hopping Of Cu2+ Ions In The Termini

The effect of Cu2+ on a-synuclein (AS) aggregation is important because clinical studies of patients with Parkinson's disease have shown elevated levels of Cu2+ in the cerebrospinal fluid. So far, the molecular architectures of Cu2+- AS fibril complexes at atomic resolution are unknown. The current work identifies for the first time that His50 cannot bind Cu2+ ions in mature fibrils. Moreover, it shows hopping of Cu2+ ions between residues in AS fibrils and changes in the Cu2+ coordination mode in Cu2+ ions that bind in the termini of AS. The current study combines extensive experimental techniques, density functional theory calculations, and computational modeling tools to provide a complete description of the Cu2+ binding site in AS fibrils. Our findings illustrate for the first time the specific interactions between Cu2+ ions and AS fibrils, suggesting a new mechanistic perspective on the effect of Cu2+ ions on AS aggregation.