Abstract
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.
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Abbreviations
- DFT:
-
Density functional theory
- PrP:
-
Prion protein
- PrPC :
-
Normal cellular form of prion protein
- PrPSc :
-
Scrapie isoform of prion protein
- SHE:
-
Standard hydrogen electrode
- SOD:
-
Superoxide dismutase
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Acknowledgments
This work was supported by the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO) and by a Grant-in-Aid for Young Scientists (B) from the Ministry of Education, Culture, Sports, Science and Technology (no. 20750008). The numerical calculations were performed using the Research Center for Computational Science (RCCS), National Institute of Natural Sciences (NINS), Okazaki, Japan, and the Information Technology Center, Nagoya University, Japan.
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Yamamoto, N., Kuwata, K. Difference in redox behaviors between copper-binding octarepeat and nonoctarepeat sites in prion protein. J Biol Inorg Chem 14, 1209–1218 (2009). https://doi.org/10.1007/s00775-009-0564-y
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DOI: https://doi.org/10.1007/s00775-009-0564-y