Fibrils of α-Synuclein Abolish the Affinity of Cu-Binding Site to His50 and Induce Hopping of Cu Ions in the Termini.

The effect of Cu on α-synuclein (AS) aggregation is important because clinical studies of patients with Parkinson's disease have shown elevated levels of Cu in the cerebrospinal fluid. So far, the molecular architectures of Cu-AS fibril complexes at atomic resolution are unknown. The current work identifies for the first time that His50 cannot bind Cu ions in mature fibrils. Moreover, it shows hopping of Cu ions between residues in AS fibrils and changes in the Cu coordination mode in Cu 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 Cu binding site in AS fibrils. Our findings illustrate for the first time the specific interactions between Cu ions and AS fibrils, suggesting a new mechanistic perspective on the effect of Cu ions on AS aggregation.