Department of Physics, Emory University, Atlanta, Georgia 30322, USA.
J Am Chem Soc. 2012 Nov 7;134(44):18330-7. doi: 10.1021/ja306946q. Epub 2012 Oct 24.
The amyloid-β (Aβ) protein forms fibrils and higher-order plaque aggegrates in Alzheimer's disease (AD) brain. The copper ion, Cu(2+), is found at high concentrations in plaques, but its role in AD etiology is unclear. We use high-resolution pulsed electron paramagnetic resonance spectroscopy to characterize the coordination structure of Cu(2+) in the fibrillar form of full-length Aβ(1-40). The results reveal a bis-cis-histidine (His) equatorial Cu(2+) coordination geometry and participation of all three N-terminal His residues in Cu(2+) binding. A model is proposed in which Cu(2+)-His6/His13 and Cu(2+)-His6/His14 sites alternate along the fibril axis on opposite sides of the β-sheet fibril structure. The local intra-β-strand coordination structure is not conducive to Cu(2+)/Cu(+) redox-linked coordination changes, and the global arrangement of Cu sites precludes facile multielectron and bridged-metal site reactivity. This indicates that the fibrillar form of Aβ suppresses Cu redox cycling and reactive oxygen species production. The configuration suggests application of Cu(2+)-Aβ fibrils as an amyloid architecture for switchable electron charge/spin coupling and redox reactivity.
淀粉样蛋白-β（Aβ）蛋白在阿尔茨海默病（AD）脑中形成纤维和更高阶的斑块聚集物。铜离子，Cu（2+），在斑块中浓度很高，但它在 AD 发病机制中的作用尚不清楚。我们使用高分辨率脉冲电子顺磁共振波谱来描述全长 Aβ（1-40）纤维形式中 Cu（2+）的配位结构。结果表明，Cu（2+）具有双顺式-组氨酸（His）赤道配位几何形状，并且所有三个 N 端 His 残基都参与 Cu（2+）结合。提出了一个模型，其中 Cu（2+）-His6/His13 和 Cu（2+）-His6/His14 位点沿着β-片层纤维结构的相反侧在纤维轴上交替排列。局部的β-链内配位结构不利于 Cu（2+）/Cu（+）氧化还原相关的配位变化，而 Cu 位点的整体排列则排除了易于发生的多电子和桥连金属位点反应性。这表明 Aβ 的纤维形式抑制了 Cu 的氧化还原循环和活性氧物质的产生。这种构型表明，Cu（2+）-Aβ 纤维可作为一种可切换电子电荷/自旋耦合和氧化还原反应性的淀粉样蛋白结构。
