Stabilization of a beta-hairpin in monomeric Alzheimer´s amyloid beta-peptide inhibits amyloid formation
2008 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, no 13, 5099-5104 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2008. Vol. 105, no 13, 5099-5104 p.
Aβ-peptide, engineered binding protein, molecular recognition, protein structure, nuclear magnetic resonance
IdentifiersURN: urn:nbn:se:kth:diva-8128DOI: 10.1073/pnas.0711731105ISI: 000254723700027ScopusID: 2-s2.0-42449111198OAI: oai:DiVA.org:kth-8128DiVA: diva2:13366
QC 201007222008-03-192008-03-192010-07-28Bibliographically approved