Effects of Familial Alzheimer’s Disease Mutations on the Assembly of a β-Hairpin Peptide Derived from Aβ16–36Click to copy article linkArticle link copied!
- Kate J. McKnellyKate J. McKnellyDepartment of Chemistry, University of California Irvine, Irvine, California 92697, United StatesMore by Kate J. McKnelly
- Adam G. KreutzerAdam G. KreutzerDepartment of Chemistry, University of California Irvine, Irvine, California 92697, United StatesMore by Adam G. Kreutzer
- William J. HowitzWilliam J. HowitzDepartment of Chemistry, University of California Irvine, Irvine, California 92697, United StatesMore by William J. Howitz
- Katelyn HaduongKatelyn HaduongDepartment of Chemistry, University of California Irvine, Irvine, California 92697, United StatesMore by Katelyn Haduong
- Stan YooStan YooDepartment of Chemistry, University of California Irvine, Irvine, California 92697, United StatesMore by Stan Yoo
- Candace HartCandace HartDepartment of Chemistry, University of California Irvine, Irvine, California 92697, United StatesMore by Candace Hart
- James S. Nowick*James S. Nowick*Email: [email protected]Department of Chemistry, University of California Irvine, Irvine, California 92697, United StatesDepartment of Pharmaceutical Sciences, University of California Irvine, Irvine, California 92697, United StatesMore by James S. Nowick
Abstract
Familial Alzheimer’s disease (FAD) is associated with mutations in the β-amyloid peptide (Aβ) or the amyloid precursor protein (APP). FAD mutations of Aβ were incorporated into a macrocyclic peptide that mimics a β-hairpin to study FAD point mutations K16N, A21G, E22Δ, E22G, E22Q, E22K, and L34V and their effect on assembly, membrane destabilization, and cytotoxicity. The X-ray crystallographic structures of the four E22 mutant peptides reveal that the peptides assemble to form the same compact hexamer. Sodium dodecyl sulphate–polyacrylamide gel electrophoresis (SDS-PAGE) experiments reveal that the mutant FAD peptides assemble as trimers or hexamers, with peptides that have greater positive charge assembling as more stable hexamers. Mutations that increase the positive charge also increase the cytotoxicity of the peptides and their propensity to destabilize lipid membranes.
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This article is cited by 9 publications.
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(16)
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(4)
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(1)
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(13)
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(10)
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(11)
, 2002-2013. https://doi.org/10.1016/j.bpj.2022.05.007
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