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

Samdin, Tuan D.; Jones, Chelsea R.; Guaglianone, Gretchen; Kreutzer, Adam G.; Freites, J. Alfredo; Wierzbicki, Michał; Nowick, James S.

doi:10.1039/d3sc05185d

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

Journal Article · 28 November 2023 · Chemical Science

DOI: https://doi.org/10.1039/d3sc05185d · OSTI ID:2228786

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University of California, Irvine, CA (United States)

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.

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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); Ministry of Science and Higher Education (MNiSW); USDOE

Grant/Contract Number:: AC02-76SF00515; GM09756; AG072587; 1647/MOB/V/2017/0

OSTI ID:: 2228786

Alternate ID(s):: OSTI ID: 2471728

Journal Information:: Chemical Science, Vol. 15, Issue 1; ISSN 2041-6520

Publisher:: Royal Society of ChemistryCopyright Statement

Country of Publication:: United States

Language:: English

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Chemistry

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

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