A ß-barrel-like tetramer formed by a ß-hairpin derived from Aß.
Chem Sci
; 15(1): 285-297, 2023 Dec 20.
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| MEDLINE
| ID: mdl-38131075
ABSTRACT
ß-Hairpins formed by the ß-amyloid peptide Aß are building blocks of Aß oligomers. Three different alignments of ß-hairpins have been observed in the structures of Aß oligomers or fibrils. Differences in ß-hairpin alignment likely contribute to the heterogeneity of Aß oligomers and thus impede their study at high-resolution. Here, we designed, synthesized, and studied a series of ß-hairpin peptides derived from Aß12-40 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 Aß residues 12-14 and 38-40 as part of an extended ß-hairpin conformation. X-ray crystallographic studies of one peptide from this series reveal the formation of ß-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 ß-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 Aß may assemble into oligomers and supports the hypothesis that ß-hairpin alignment and topology may contribute directly to oligomer heterogeneity.
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01-internacional
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MEDLINE
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En
Revista:
Chem Sci
Año:
2023
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Article