Data from: Site-specific structural order in Alzheimer’s Aβ42 fibrils

Deposition of amyloid fibrils is a pathological hallmark of Alzheimer’s disease. Aβ42 is the major protein whose aggregation leads to the formation of these fibrils. Understanding the detailed structure of Aβ42 fibrils is of particular importance for delineating the mechanism of Aβ42 aggregation and developing specific amyloid-targeting drugs. Here we use site-directed spin labeling and electron paramagnetic resonance spectroscopy to study the site-specific structural order at each and every residue position in Aβ42 fibrils. Strong interactions between spin labels indicate highly ordered protein backbone at the labeling site, while weak interactions suggest disordered local structure. Our results show that Aβ42 consists of 5 β-strands (residues 2-7, 10-13, 17-20, 31-36, 39-41), 3 turns (residues 7-8, 14-16, 37-38), and 1 ordered loop (residues 21-30). Spin labels introduced at β-strand sites show strong spin-spin interactions, while spin labels at turn or loop sites show weak interactions. However, residues 24, 25, and 28 also show strong interactions between spin labels, suggesting that the loop 21-30 is partly ordered. In the context of recent structural work using solid-state NMR and cryoEM, the site-specific structural order revealed in this study provides a different perspective on backbone and side chain dynamics of Aβ42 fibrils.淀粉样纤维沉积是阿尔茨海默病的病理性标志性特征。β淀粉样蛋白42（Aβ42）是介导其聚集形成此类纤维的主要蛋白。解析Aβ42纤维的精细结构，对于阐明Aβ42聚集的分子机制、开发靶向淀粉样蛋白的特异性药物均具有重要的科学价值。本研究采用定点自旋标记（site-directed spin labeling）技术与电子顺磁共振波谱（electron paramagnetic resonance spectroscopy）技术，对Aβ42纤维中每一个残基位点的位点特异性结构有序性展开研究。自旋标记物之间的强相互作用，提示标记位点处的蛋白质主链处于高度有序状态；而弱相互作用则表明该位点的局部结构存在无序性。本研究结果显示，Aβ42纤维由5个β折叠链（残基2-7、10-13、17-20、31-36、39-41）、3个转角（残基7-8、14-16、37-38）以及1个有序环结构（残基21-30）构成。在β折叠链位点引入的自旋标记物可检测到较强的自旋-自旋相互作用，而位于转角或环结构位点的自旋标记物则表现出较弱的相互作用。不过，残基24、25和28同样呈现出较强的自旋标记物间相互作用，这提示21-30位的环结构存在部分有序性。结合近期利用固体核磁共振（solid-state NMR）与冷冻电子显微镜（cryoEM）开展的结构研究，本研究所揭示的位点特异性结构有序性，为理解Aβ42纤维的主链与侧链动态特性提供了全新视角。