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α-Synuclein (αSyn) forms amyloid fibrils in the neurons of Parkinson's disease (PD) patients'. Despite a role for Cu 2+ in accelerating αSyn fibril formation, coupled with reports of copper dis-homeostasis in PD, there remain controversies surrounding the coordination geometry of Cu 2+ with αSyn. Here we compare visible circular dichroism (CD) spectra of Cu 2+ loaded on to full-length αSyn together with four peptides that model aspects of Cu 2+ binding to the N-terminus and histidine50 of αSyn. With glycine as a competitive ligand, the affinity of Cu 2+ for full-length αSyn is determined to have a conditional dissociation constant, at pH 7.4, of 0.1 nM. A similar affinity of 0.3 nM is determined for the tripeptide Met-Asp-Val(MDV) that mimics the N-terminus of αSyn, while the incorporation of a putative histidine side chain in the N-terminal complex facilitates the formation of a macrochelate with the histidine, which results in an increase in the affinity for Cu 2+ o 0.03 nM at pH 7.4. Comparisons of the visible absorbance and CD spectra over a range of pH values also indicates that the MDV tripeptide closely models Cu 2+ binding to full-length αSyn and rules out a role for His50 in the primary Cu 2+ binding complex of monomeric αSyn. However, there are reports that suggest His50 does form a macrochelate with the N-terminal Cu 2+ complex; we reconcile these conflicting observations by identifying a concentration dependence of the interaction. Only at the higher concentrations can the imidazole nitrogen bind to the N-terminal Cu 2+ o form a ternary complex rather than via a macrochelate. This work shows even for this intrinsically disordered protein a large macrochelate with Cu 2+ is not favored. Understanding Cu 2+ coordination to αSyn gives a more complete picture of its place in amyloid assembly and cytotoxicity.

Copper2+ Binding to α-Synuclein. Histidine50 Can Form a Ternary Complex with Cu2+ at the N-Terminus but Not a Macrochelate

Copper²⁺ Binding to α-Synuclein. Histidine50 Can Form a Ternary Complex with Cu²⁺ at the N-Terminus but Not a Macrochelate