Hoyer Wolfgang, Grönwall Caroline, Jonsson Andreas, Ståhl Stefan, Härd Torleif
Department of Medical Biochemistry and Swedish Nuclear Magnetic Resonance Center, University of Gothenburg, Box 440, SE-405 30 Göteborg, Sweden.
Proc Natl Acad Sci U S A. 2008 Apr 1;105(13):5099-104. doi: 10.1073/pnas.0711731105. Epub 2008 Mar 28.
According to the amyloid hypothesis, the pathogenesis of Alzheimer's disease is triggered by the oligomerization and aggregation of the amyloid-beta (Abeta) peptide into protein plaques. Formation of the potentially toxic oligomeric and fibrillar Abeta assemblies is accompanied by a conformational change toward a high content of beta-structure. Here, we report the solution structure of Abeta(1-40) in complex with the phage-display selected affibody protein Z(Abeta3), a binding protein of nanomolar affinity. Bound Abeta(1-40) features a beta-hairpin comprising residues 17-36, providing the first high-resolution structure of Abeta in beta conformation. The positions of the secondary structure elements strongly resemble those observed for fibrillar Abeta. Z(Abeta3) stabilizes the beta-sheet by extending it intermolecularly and by burying both of the mostly nonpolar faces of the Abeta hairpin within a large hydrophobic tunnel-like cavity. Consequently, Z(Abeta3) acts as a stoichiometric inhibitor of Abeta fibrillation. The selected Abeta conformation allows us to suggest a structural mechanism for amyloid formation based on soluble oligomeric hairpin intermediates.
根据淀粉样蛋白假说，阿尔茨海默病的发病机制是由β淀粉样蛋白（Aβ）肽寡聚化并聚集成蛋白斑块所引发的。具有潜在毒性的寡聚体和纤维状Aβ聚集体的形成伴随着向高含量β结构的构象变化。在此，我们报道了与噬菌体展示筛选出的亲和体蛋白Z（Aβ3）（一种具有纳摩尔亲和力的结合蛋白）结合的Aβ（1-40）的溶液结构。结合的Aβ（1-40）具有一个由17至36位残基组成的β发夹结构，提供了处于β构象的Aβ的首个高分辨率结构。二级结构元件的位置与在纤维状Aβ中观察到的位置非常相似。Z（Aβ3）通过分子间扩展β折叠并将Aβ发夹结构的两个主要非极性面掩埋在一个大的疏水隧道样腔体内来稳定β折叠。因此，Z（Aβ3）作为Aβ纤维化的化学计量抑制剂发挥作用。所选择的Aβ构象使我们能够基于可溶性寡聚发夹中间体提出一种淀粉样蛋白形成的结构机制。
