Stabilization of a β-hairpin in monomeric Alzheimer's amyloid-β peptide inhibits amyloid formation
Stabilization of a β-hairpin in monomeric Alzheimer's amyloid-β peptide inhibits amyloid formation
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DOI：
10.1073/pnas.0711731105
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发表时间：
2008-04-01
影响因子：
11.1
通讯作者：
Hard, Torleif
中科院分区：
文献类型：
--
作者：
Hoyer, Wolfgang;Gronwall, Caroline;Hard, Torleif
根据淀粉样蛋白假说，阿尔茨海默病的发病机制是由淀粉样蛋白- β (A β)肽寡聚化和聚集成蛋白质斑块引发的。具有潜在毒性的低聚物和纤维A β组装体的形成伴随着向高含量β结构的构象变化。在这里，我们报道了A β(1-40)与噬菌体展示选择的粘附蛋白Z(A1 β 3)（一种纳米摩尔亲和力的结合蛋白）复合物的溶液结构。结合的A β(1-40)具有包含残基17-36的β发夹，提供了β构象的A β的第一个高分辨率结构。二级结构元素的位置与原纤维A β的位置非常相似。Z（A β 3）通过在分子间扩展和将A β发夹的大部分非极性面埋在一个大的疏水隧道状腔内来稳定β -片。因此，Z（A β 3）作为A β纤颤的化学计量抑制剂。选择的A β构象使我们能够提出一种基于可溶性低聚发夹中间体的淀粉样蛋白形成的结构机制。
According to the amyloid hypothesis, the pathogenesis of Alzheimer's disease is triggered by the oligomerization and aggregation of the amyloid-beta (A beta) peptide into protein plaques. Formation of the potentially toxic oligomeric and fibrillar A beta assemblies is accompanied by a conformational change toward a high content of beta-structure. Here, we report the solution structure of A beta(1-40) in complex with the phage-display selected affibody protein Z(A1 beta 3), a binding protein of nanomolar affinity. Bound A beta(1-40) features a beta-hairpin comprising residues 17-36, providing the first high-resolution structure of A beta in beta conformation. The positions of the secondary structure elements strongly resemble those observed for fibrillar A beta. Z(A beta 3) stabilizes the beta-sheet by extending it inter-molecularly and by burying both of the mostly nonpolar faces of the A beta hairpin within a large hydrophobic tunnel-like cavity. Consequently, Z(A beta 3) acts as a stoichiometric inhibitor of A beta fibrillation. The selected A beta conformation allows us to suggest a structural mechanism for amyloid formation based on soluble oligomeric hairpin intermediates.