National Research Council of Italy (CNR), Institute for Chemistry of Organometallic Compounds (ICCOM), via Madonna del Piano 10, 50019 Sesto Fiorentino, Firenze, Italy.
Phys Chem Chem Phys. 2019 Apr 24;21(17):8774-8784. doi: 10.1039/c9cp00293f.
Amyloid-β (Aβ) peptides are intrinsically disordered peptides and their aggregation is the major hallmark of Alzheimer's disease (AD) development. The interactions between copper ions and Aβ peptides create catalysts that activate the production of reactive oxygen species in the synaptic region, a reactivity that is strongly related to AD onset. Recent experimental work [Gu et al., Sci. Rep., 2018, 8(1), 16190] confirmed that the oxidative reactivity of Cu-Aβ catalyzes the formation of Tyr-Tyr crosslinks in peptide dimers. This work provides a structural basis to these observations, describing structures of Cu-Aβ dimers that enhance the propagation of the oxidative pathways activated around the Cu center. Among these, the formation of Tyr-Tyr crosslinks becomes more likely when previous crosslinks involve Cu forming bridges between different peptides. Peptides are, therefore, easily assembled into dimers and tetramers, the latter being dimers of dimers. The size of such dimers and tetramers fits with ion mobility mass spectrometry results [Sitkiewicz et al., J. Mol. Biol., 2014, 426(15), 2871].
淀粉样蛋白-β（Aβ）肽是无规卷曲的肽，其聚集是阿尔茨海默病（AD）发展的主要标志。铜离子与 Aβ 肽之间的相互作用产生了催化剂，这些催化剂激活了突触区域中活性氧物质的产生，这种活性与 AD 的发病密切相关。最近的实验工作[Gu 等人，Sci. Rep.，2018，8（1），16190]证实，Cu-Aβ的氧化反应性催化了肽二聚体中 Tyr-Tyr 交联的形成。这项工作为这些观察结果提供了结构基础，描述了 Cu-Aβ二聚体的结构，这些结构增强了围绕 Cu 中心激活的氧化途径的传播。在这些结构中，当先前的交联涉及 Cu 在不同肽之间形成桥时，Tyr-Tyr 交联的形成变得更加可能。因此，肽很容易组装成二聚体和四聚体，后者是二聚体的二聚体。这些二聚体和四聚体的大小与离子淌度质谱结果[Sitkiewicz 等人，J. Mol. Biol.，2014，426（15），2871]相符。
