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

朊蛋白（PrP）是一种金属蛋白，其n端半结构域具有多个铜结合区。一个是PrP中高度保守的八肽重复部分（60-91）。其他的铜结合位点位于His96和His111周围。在本研究中，为了阐明铜在朊病毒疾病的病理机制中的作用，我们利用密度泛函理论计算研究了PrP中这些铜结合位点的氧化还原化学行为。结果表明，8个重复位点具有较高的Cu(II)/Cu(I)还原电位，具有类似sod的活性。然而，结合在His96和His111位点上的铜离子具有较高的Cu(II)/Cu（III）氧化电位，可以通过fenton型促氧化反应修饰氧化还原性质，与过氧化氢反应生成羟基自由基。PrP的这些不同的氧化还原活性，单独或集体，可能参与了朊病毒疾病的神经毒性机制。

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.