通过E22开关控制的阿尔茨海默病β-粉样纤维的结构多态性:固态NMR研究
Matthew R Elkins1, Tuo Wang1, Mimi Nick2
1Department of Chemistry, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.
Journal of the American Chemical Society
|July 15, 2016
概括
在阿尔茨海默病 (AD) 纤维细胞中,粉样β (Aβ) 的北极E22G突变导致显著的结构多态性,揭示了基于内在序列的结构变异. 这些发现突显了静电相互作用在Aβ纤维素形成和AD病变发生中的作用.
科学领域:
- 神经科学
- 生物化学
- 结构生物学
背景情况:
- 阿尔茨海默病 (AD) 的特征是粉样β (Aβ) 纤维的形成.
- 观察到Aβ纤维的多态性,但其氨基酸序列的基础不明.
- E22G (北极) 突变与家族性阿尔茨海默病有关,并影响纤维细胞的形成.
研究的目的:
- 研究北极E22G Aβ40纤维的结构,动态,水分和形态.
- 将北极E22G Aβ40纤维与野生型和大阪E22Δ Aβ40纤维进行比较.
- 确定Aβ纤维素多态性的内在序列基础.
主要方法:
- 使用 (13) C, (15) N 标记合成 Aβ40 的固态核磁共振光谱.
- 来自二维相关谱的NMR化学转移和残留间接触的分析.
- 测量 (13) C- ((1) H 二极顺序参数, (1) H 旋转框架旋转放松时间,以及水与蛋白质的旋转扩散.
主要成果:
- 北极E22G Aβ40纤维具有显著的结构多态性,至少有四组NMR化学转移.
- 野生型和大阪 E22Δ Aβ40 纤维呈现单一或主要的一组化学转移.
- 一个主要的北极适应者与野生型Aβ42具有结构的相似性;动态和水分在各个变体之间存在很大差异.
结论:
- 粉样β纤维的结构多态性是北极E22G Aβ40序列的内在特征.
- 在Aβ序列中的静电相互作用对纤维的折叠至关重要.
- 纤维结构影响神经元毒性和阿尔茨海默病的发病.
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