Roles of Metallic Ions in Prion Diseases : Structure and Properties of Copper-binding Sites in Prion Protein

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Prion protein (PrP) is a metalloprotein having several copper-binding regions in the N-terminal half domain. One is a highly conserved octapeptide repeat portion in PrP(60-91). Additional copper-binding sites are located around His96 and His111. In this study, to clarify copper's role in the pathological mechanism underlying prion diseases, we had investigated redox chemical behaviors of these copper-binding sites in PrP using the density functional theory calculations. The results indicated that the octarepeat sites had a high Cu(II)/Cu(I) reduction potential, which can exhibit SOD-like activity. The copper ion bound to the His96 and His111 sites, however, had a high Cu(II)/Cu(III) oxidation potential, which can modify the redox property to react with hydrogen peroxide to generate hydroxyl radicals via a Fenton-type pro-oxidative reaction. These distinct redox activities of PrP, individually or collectively, could be involved in the neurotoxic mechanism underlying prion diseases.