Stabilization of a β-hairpin in monomeric Alzheimer's amyloid-β peptide inhibits amyloid formation
2008
Hoyer, Wolfgang | Grönwall, Caroline | Jonsson, Andreas | Ståhl, Stefan | Härd, Torleif
According to the amyloid hypothesis, the pathogenesis of Alzheimer's disease is triggered by the oligomerization and aggregation of the amyloid-β (Aβ) peptide into protein plaques. Formation of the potentially toxic oligomeric and fibrillar Aβ assemblies is accompanied by a conformational change toward a high content of β-structure. Here, we report the solution structure of Aβ(1-40) in complex with the phage-display selected affibody protein ZAβ₃, a binding protein of nanomolar affinity. Bound Aβ(1-40) features a β-hairpin comprising residues 17-36, providing the first high-resolution structure of Aβ in β conformation. The positions of the secondary structure elements strongly resemble those observed for fibrillar Aβ. ZAβ₃ stabilizes the β-sheet by extending it intermolecularly and by burying both of the mostly nonpolar faces of the Aβ hairpin within a large hydrophobic tunnel-like cavity. Consequently, ZAβ₃ acts as a stoichiometric inhibitor of Aβ fibrillation. The selected Aβ conformation allows us to suggest a structural mechanism for amyloid formation based on soluble oligomeric hairpin intermediates.
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