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

doi:10.1073/pnas.0711731105

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

*Department of Medical Biochemistry and Swedish Nuclear Magnetic Resonance Center, University of Gothenburg, Box 440, SE-405 30 Göteborg, Sweden;
^†Department of Molecular Biotechnology, School of Biotechnology, AlbaNova University Center, Royal Institute of Technology, SE-106 91 Stockholm, Sweden; and
^‡Affibody AB, Box 20137, SE-161 02 Bromma, Sweden

Edited by Adriaan Bax, National Institutes of Health, Bethesda, MD, and approved February 1, 2008 (received for review December 13, 2007)

Abstract

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 Z_Aβ3, 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. Z_Aβ3 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, Z_Aβ3 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.

Footnotes

^§To whom correspondence should be addressed. E-mail: torleif.hard{at}gu.se
Author contributions: W.H. and T.H. designed research; W.H., C.G., A.J., S.S., and T.H. performed research; C.G., A.J., and S.S. contributed new reagents/analytic tools; W.H. and T.H. analyzed data; and W.H. and T.H. wrote the paper.
Conflict of interest statement: A.J. is an employee of Affibody AB.
This article is a PNAS Direct Submission.
Data deposition: Atomic coordinates and experimental constraints have been deposited in the Protein Data Bank, www.pdb.org [accession no. 2OTK (Z_Aβ3:Aβ(1–40) complex)].
This article contains supporting information online at www.pnas.org/cgi/content/full/0711731105/DCSupplemental.