Girvan Paul, Miyake Toru, Teng Xiangyu, Branch Thomas, Ying Liming
Institute of Chemical Biology, Imperial College London, Exhibition Road, London, SW7 2AZ, UK.
Department of Chemistry, Imperial College London, Exhibition Road, London, SW7 2AZ, UK.
Chembiochem. 2016 Sep 15;17(18):1732-7. doi: 10.1002/cbic.201600255. Epub 2016 Aug 2.
Mutations and post-translational modifications of amyloid-β (Aβ) peptide in its N terminus have been shown to increase fibril formation, yet the molecular mechanism is not clear. Here we investigated the kinetics of the interactions of copper with two Aβ peptides containing Familial Alzheimer's disease (FAD) mutations (English (H6R) and Tottori (D7N)), as well as with Aβ peptide phosphorylated at serine 8 (pS8). All three peptides bind to copper with a similar rate as the wild-type (wt). The dissociation rates follow the order pS8>H6R>wt>D7N; the interconversion between the two coordinating species occurs 50 % faster for H6R and pS8, whereas D7N had only a negligible effect. Interestingly, the rate of ternary complex (copper-bridged heterodimer) formation for the modified peptides was significantly faster than that for wt, thus leading us to propose that FAD and sporadic AD might share a kinetic origin for the enhanced oligomerisation of Aβ.
淀粉样β蛋白（Aβ）肽N端的突变和翻译后修饰已被证明会增加纤维形成，但其分子机制尚不清楚。在此，我们研究了铜与两种含有家族性阿尔茨海默病（FAD）突变的Aβ肽（英国突变体（H6R）和鸟取突变体（D7N））以及丝氨酸8位点磷酸化的Aβ肽（pS8）相互作用的动力学。所有这三种肽与铜结合的速率与野生型（wt）相似。解离速率顺序为pS8>H6R>wt>D7N；对于H6R和pS8，两种配位物种之间的相互转化速度快50%，而D7N的影响可忽略不计。有趣的是，修饰肽形成三元复合物（铜桥连异二聚体）的速率明显快于野生型，因此我们提出FAD和散发性AD可能在Aβ增强寡聚化方面有共同的动力学起源。
