Yifat Miller

The effect of Cu²⁺ on α-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.