The Copper(II) Adduct of the Unstructured Region of the Amyloidogenic Fragment Derived from theHuman 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{sup 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{sup II} binding region of PrP(91-126) is contained between residues 106 and 114. Both [Cu{sup II}(PrP(91-126))] and [Cu{sup II}(PrP(106-114))] have Cu{sup II} K{sub d} values of {approx}90 {mu}M. Furthermore, the smaller PrP fragment PrP(106-114) coordinates Cu{sup II} producing an electronic absorption spectrum nearly identical with [Cu{sup II}(PrP(91-126))] ({lambda}{sub max} {approx}610 nm ({var_epsilon} {approx}125 M{sup -1} cm{sup -1})) suggesting a similar coordination environment for Cu{sup II}. Cu K-edge X-ray absorption spectroscopy (XAS) reveals a nearly identical CuN(N/O){sub 2}S coordination environment for these two metallopeptides (2N/O at {approx}1.97 {angstrom}; 1S at {approx}2.30 {angstrom}; 1 imidazole N at {approx}1.95 {angstrom}). Both display quasireversible Cu{sup II}/Cu{sup I} redox couples at {approx}-350 mV vs Ag/AgCl. ESI-MS indicates that both peptides will coordinate Cu{sup I}. However, XAS indicates differential coordination environments between [Cu{sup I}(PrP(91-126))] and [Cu{sup I}(PrP(106-114))]. These data indicate that [Cu{sup I}(PrP(91-126))] contains Cu in a four coordinate (N/O){sub 2}S{sub 2} environment with similar (N/O)-Cu bond distances (Cu-(N/O) r = 2.048(4) {angstrom}), while [Cu{sup I}(PrP(106-114))] contains Cu in a four coordinate (N/O){sub 2}S{sub 2} environment with differential (N/O)-Cu bond distances (Cu-(N/O) r{sub 1} = 2.057(6) {angstrom}; r{sub 2} = 2.159(3) {angstrom}). Despite the differential coordination environments both Cu-metallopeptides will catalytically reduce O{sub 2} to O{sub 2}{sup {sm_bullet}-} at comparable rates.
- Research Organization:
- Brookhaven National Lab. (BNL), Upton, NY (United States). National Synchrotron Light Source
- Sponsoring Organization:
- Doe - Office Of Science
- DOE Contract Number:
- DE-AC02-98CH10886
- OSTI ID:
- 930323
- Report Number(s):
- BNL-81033-2008-JA; INOCAJ; TRN: US200904%%620
- Journal Information:
- Inorganic Chemistry, Vol. 46, Issue 3; ISSN 0020-1669
- Country of Publication:
- United States
- Language:
- English
Similar Records
Ni K-Edge XAS Suggests that Coordination of Ni II to the Unstructured Amyloidogenice Region of the Human Prion Protein Produces a Ni2 bis-u-hydroxo Dimer
Influence of Amide/Amine vs Nis-Amide Coordination in Nickel Superoxide Dismutase