Difference in redox behaviors between copper-binding octarepeat and nonoctarepeat sites in prion protein.
We studied the redox behavior of copper-binding sites in prion protein (PrP) to clarify copper's role in the pathological mechanism underlying prion diseases. We investigated the coordination structures, binding affinities, and redox potentials of copper-binding peptide fragments derived from the N-terminal domain of PrP by density functional theory calculations. We used four models for copper-binding moieties in PrP(60-96): two were derived from the PHGGGWGQ octapeptide repeat region of PrP(60-91), and the others were tripeptide Gly-Thr-His fragments derived from the copper-binding nonoctarepeat site around His96. We found that such PrP-derived copper-binding complexes exhibit conformationally dependent redox behavior; for example, the copper-binding complex derived from the octarepeat region tends to possess high reduction potential for the Cu(II)/Cu(I) couple, exceeding 0 V versus the standard hydrogen electrode, whereas the copper-binding nonoctarepeat model around His96 tends to possess high oxidation potential for the Cu(II)/Cu(III) couple and stabilize the higher-valent Cu(III) state. It is possible that such distinct redox activities of a copper-binding PrP are involved in the mechanism underlying prion diseases.
Yamamoto
Norifumi
N
Division of Prion Research, Center for Emerging Infectious Diseases, Gifu University, Gifu 501-1194, Japan. yamamoto@gifu-u.ac.jp
Kuwata
Kazuo
K
D000818:Animals; D001665:Binding Sites; D003300:Copper / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017096:Prion Diseases / Q000503:physiopathology; D011328:Prions / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D020449:Repetitive Sequences, Amino Acid; D015032:Zinc / Q000737:chemistry
D010446:Peptide Fragments; D011328:Prions; D003300:Copper; D015032:Zinc