Dataset Information

Effects of Familial Alzheimer's Disease Mutations on the Assembly of a β-Hairpin Peptide Derived from Aβ_16-36.

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.

SUBMITTER: McKnelly KJ

PROVIDER: S-EPMC9042424 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Publications

Effects of Familial Alzheimer's Disease Mutations on the Assembly of a β-Hairpin Peptide Derived from Aβ<sub>16-36</sub>.

McKnelly Kate J KJ Kreutzer Adam G AG Howitz William J WJ Haduong Katelyn K Yoo Stan S Hart Candace C Nowick James S JS

Biochemistry 20220225 6

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 ...[more]

PMID: 35213141

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Project description:Clinical studies have identified a correlation between type-2 diabetes mellitus and cognitive decrements en route to the onset of Alzheimer's disease (AD). Recent studies have established that post-translational modifications of the amyloid β (Aβ) peptide occur under hyperglycemic conditions; particularly, the process of glycation exacerbates its neurotoxicity and accelerates AD progression. In view of the assertion that macromolecular crowding has an altering effect on protein self-assembly, it is crucial to characterize the effects of hyperglycemic conditions via crowding on Aβ self-assembly. Toward this purpose, fully atomistic molecular dynamics simulations were performed to study the effects of glucose crowding on Aβ dimerization, which is the smallest known neurotoxic species. The dimers formed in the glucose-crowded environment were found to have weaker associations as compared to that of those formed in water. Binding free energy calculations show that the reduced binding strength of the dimers can be mainly attributed to the overall weakening of the dispersion interactions correlated with substantial loss of interpeptide contacts in the hydrophobic patches of the Aβ units. Analysis to discern the differential solvation pattern in the glucose-crowded and pure water systems revealed that glucose molecules cluster around the protein, at a distance of 5-7 Å, which traps the water molecules in close association with the protein surface. This preferential exclusion of glucose molecules and resulting hydration of the Aβ peptides has a screening effect on the hydrophobic interactions, which in turn diminishes the binding strength of the resulting dimers. Our results imply that physical effects attributed to crowded hyperglycemic environments are incapable of solely promoting Aβ self-assembly, indicating that further mechanistic studies are required to provide insights into the self-assembly of post-translationally modified Aβ peptides, known to possess aggravated toxicity, under these conditions.

Dataset Information

Effects of Familial Alzheimer's Disease Mutations on the Assembly of a β-Hairpin Peptide Derived from Aβ_16-36.

Publications

Effects of Familial Alzheimer's Disease Mutations on the Assembly of a β-Hairpin Peptide Derived from Aβ<sub>16-36</sub>.

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Dataset Information

Effects of Familial Alzheimer's Disease Mutations on the Assembly of a β-Hairpin Peptide Derived from Aβ16-36.

Publications

Effects of Familial Alzheimer's Disease Mutations on the Assembly of a β-Hairpin Peptide Derived from Aβ<sub>16-36</sub>.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Effects of Familial Alzheimer's Disease Mutations on the Assembly of a β-Hairpin Peptide Derived from Aβ_16-36.