A β-barrel-like tetramer formed by a β-hairpin derived from Aβ

β-Hairpins formed by the β-amyloid peptide Aβ are building blocks of Aβ oligomers. Three different alignments of β-hairpins have been observed in the structures of Aβ oligomers or fibrils. Differences in β-hairpin alignment likely contribute to the heterogeneity of Aβ oligomers and thus impede their...

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Bibliographic Details
Published in:Chemical science (Cambridge) 2023-12, Vol.15 (1), p.285-297
Main Authors: Samdin, Tuan D, Jones, Chelsea R, Guaglianone, Gretchen, Kreutzer, Adam G, Freites, J. Alfredo, Wierzbicki, Micha, Nowick, James S
Format: Article
Language:English
Subjects:
Alignment
Chemistry
Crystallography
Heterogeneity
Hydrogen bonding
Lipids
Membranes
Molecular dynamics
Oligomers
Peptides
Topology
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Summary:β-Hairpins formed by the β-amyloid peptide Aβ are building blocks of Aβ oligomers. Three different alignments of β-hairpins have been observed in the structures of Aβ oligomers or fibrils. Differences in β-hairpin alignment likely contribute to the heterogeneity of Aβ oligomers and thus impede their study at high-resolution. Here, we designed, synthesized, and studied a series of β-hairpin peptides derived from Aβ 12-40 in one of these three alignments and investigated their solution-phase assembly and folding. These assays reveal the formation of tetramers and octamers that are stabilized by intermolecular hydrogen bonding interactions between Aβ residues 12-14 and 38-40 as part of an extended β-hairpin conformation. X-ray crystallographic studies of one peptide from this series reveal the formation of β-barrel-like tetramers and octamers that are stabilized by edge-to-edge hydrogen bonding and hydrophobic packing. Dye-leakage and caspase 3/7 activation assays using tetramer and octamer forming peptides from this series reveal membrane-damaging and apoptotic properties. A molecular dynamics simulation of the β-barrel-like tetramer embedded in a lipid bilayer shows membrane disruption and water permeation. The tetramers and octamers described herein provide additional models of how Aβ may assemble into oligomers and supports the hypothesis that β-hairpin alignment and topology may contribute directly to oligomer heterogeneity. β-Hairpins formed by the β-amyloid peptide Aβ are building blocks of Aβ oligomers.
ISSN:2041-6520
2041-6539
DOI:10.1039/d3sc05185d