The Copper(II) Adduct of the Unstructured Region of the Amyloidogenic Fragment Derived from the Human Prion Protein is Redox-Active at Physiological pH

Prion diseases are caused by the misfolding and aggregation of the prion protein (PrP). Herein we provide evidence that the Cu^II adduct of the unstructured amyloidogenic fragment of the human PrP (PrP(91−126)) is redox active under physiological conditions. We have identified that the relevant high-affinity Cu^II binding region of PrP(91−126) is contained between residues 106 and 114. Both [Cu^II(PrP(91−126))] and [Cu^II(PrP(106−114))] have Cu^II K_d values of ∼90 μM. Furthermore, the smaller PrP fragment PrP(106−114) coordinates Cu^II producing an electronic absorption spectrum nearly identical with [Cu^II(PrP(91−126))] (λ_max ∼ 610 nm (ε ∼ 125 M^-1 cm^-1)) suggesting a similar coordination environment for Cu^II. Cu K-edge X-ray absorption spectroscopy (XAS) reveals a nearly identical CuN(N/O)₂S coordination environment for these two metallopeptides (2N/O at ∼1.97 Å; 1S at ∼ 2.30 Å; 1 imidazole N at ∼1.95 Å). Both display quasireversible Cu^II/Cu^I redox couples at ∼−350 mV vs Ag/AgCl. ESI-MS indicates that both peptides will coordinate Cu^I. However, XAS indicates differential coordination environments between [Cu^I(PrP(91−126))] and [Cu^I(PrP(106−114))]. These data indicate that [Cu^I(PrP(91−126))] contains Cu in a four coordinate (N/O)₂S₂ environment with similar (N/O)−Cu bond distances (Cu−(N/O) r = 2.048(4) Å), while [Cu^I(PrP(106−114))] contains Cu in a four coordinate (N/O)₂S₂ environment with differential (N/O)−Cu bond distances (Cu−(N/O) r₁ = 2.057(6) Å; r₂ = 2.159(3) Å). Despite the differential coordination environments both Cu-metallopeptides will catalytically reduce O₂ to O₂^•- at comparable rates.