Stabilization of a β-hairpin in monomeric Alzheimer's amyloid-β peptide inhibits amyloid formation

被引:347
|
作者
Hoyer, Wolfgang [1 ,2 ]
Gronwall, Caroline [3 ]
Jonsson, Andreas [3 ,4 ]
Stahl, Stefan [3 ]
Hard, Torleif [1 ,2 ]
机构
[1] Univ Gothenburg, Dept Med Biochem, SE-40530 Gothenburg, Sweden
[2] Univ Gothenburg, Swedish Nucl Magnet Resonance Ctr, SE-40530 Gothenburg, Sweden
[3] AlbaNova Univ Ctr, Royal Inst Technol, Sch Biotechnol, Dept Mol Biotechnol, SE-10691 Stockholm, Sweden
[4] Affibody AB, SE-16102 Bromma, Sweden
关键词
A beta-pepticle; engineered binding protein; molecular recognition; protein structure; nuclear magnetic resonance;
D O I
10.1073/pnas.0711731105
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:5099 / 5104
页数:6
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