Fibrils of α-Synuclein Abolish the Affinity of Cu²⁺-Binding Site to His50 and Induce Hopping of Cu²⁺ Ions in the Termini

Abstract

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.

Molecular Mechanisms and Aspects on the Role of Neuropeptide Y as a Zn2+ and Cu2+ Chelator

“…The computational results demonstrated excellent agreement with the experimental observations of the Zn 2+ -NKA complex. Previously, we also used the experiment-based structure of α-synuclein fibrils to construct Cu 2+ -α-synuclein fibrils . We have shown that the specific Cu 2+ binding site (His50) that was proposed by our simulations is similar to the Cu 2+ binding site that was obtained from the experimental techniques.…”

“…Previously, we also used the experimentbased structure of α-synuclein fibrils to construct Cu 2+ -αsynuclein fibrils. 40 We have shown that the specific Cu 2+ binding site (His50) that was proposed by our simulations is similar to the Cu 2+ binding site that was obtained from the experimental techniques. We are therefore confident that using the experiment-based structure of NPY and constructing metal-NPY from this structure is a reliable procedure.…”

Aggregation of biologically important peptides and proteins: inhibition or acceleration depending on protein and metal ion concentrations

“…The other region is at C-terminal part with residues Asp119, Asp121, Asn122, Glu123 and binds copper ions with low affinity. [65][66][67] For His50, the ability to bind Cu 2+ is greatly affected by pH. It was shown that lowering the pH to the acidic values cease the ability of His50 to bind copper.…”

“…68 Additionally the acetylation on N-terminal region of a-synuclein abolished its ability to bind Cu 2+ at residue Met1, leaving His50 ability intact in this region. 66,69 However, a recent paper 67 shows that copper does not bind to His50 in a-synuclein brils. Instead, during the brillation process Cu 2+ has the ability to bind to other residues in N-terminal and C-terminal sites and can "bounce" between them.…”

Using NMR spectroscopy to investigate the role played by copper in prion diseases

“…The high-affinity of copper-binding sites is located at the N- terminus with residues Met1, Asp2, and Met5. The low-affinity copper-binding sites are located at the N- terminus residue His50 or at the C-terminal part with residues Asp119, Asp121, Asn122, and Glu123 [ 78 – 80 ].…”