Dataset Information

β-Hairpin Alignment Alters Oligomer Formation in Aβ-Derived Peptides.

ABSTRACT: Amyloid-β (Aβ) forms heterogeneous oligomers, which are implicated in the pathogenesis of Alzheimer's disease (AD). Many Aβ oligomers consist of β-hairpin building blocks─Aβ peptides in β-hairpin conformations. β-Hairpins of Aβ can adopt a variety of alignments, but the role that β-hairpin alignment plays in the formation and heterogeneity of Aβ oligomers is poorly understood. To explore the effect of β-hairpin alignment on the oligomerization of Aβ peptides, we designed and studied two model peptides with two different β-hairpin alignments. Peptides Aβm_17-36 and Aβm_17-35 mimic two different β-hairpins that Aβ can form, the Aβ_17-36 and Aβ_17-35 β-hairpins, respectively. These hairpins are similar in composition but differ in hairpin alignment, altering the facial arrangements of the side chains of the residues that they contain. X-ray crystallography and SDS-PAGE demonstrate that the difference in facial arrangement between these peptides leads to distinct oligomer formation. In the crystal state, Aβm_17-36 forms triangular trimers that further assemble to form hexamers, while Aβm_17-35 forms tetrameric β-barrels. In SDS-PAGE, Aβm_17-36 assembles to form a ladder of oligomers, while Aβm_17-35 either assembles to form a dimer or does not assemble at all. The differences in the behavior of Aβm_17-36 and Aβm_17-35 suggest β-hairpin alignment as a source of the observed heterogeneity of Aβ oligomers.

SUBMITTER: Ruttenberg SM

PROVIDER: S-EPMC10795187 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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β-Hairpin Alignment Alters Oligomer Formation in Aβ-Derived Peptides.

Ruttenberg Sarah M SM Kreutzer Adam G AG Truex Nicholas L NL Nowick James S JS

Biochemistry 20240101 2

Amyloid-β (Aβ) forms heterogeneous oligomers, which are implicated in the pathogenesis of Alzheimer's disease (AD). Many Aβ oligomers consist of β-hairpin building blocks─Aβ peptides in β-hairpin conformations. β-Hairpins of Aβ can adopt a variety of alignments, but the role that β-hairpin alignment plays in the formation and heterogeneity of Aβ oligomers is poorly understood. To explore the effect of β-hairpin alignment on the oligomerization of Aβ peptides, we designed and studied two model pe ...[more]

PMID: 38163326

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Project description:Protein misfolding disorders are associated with conformational changes in specific proteins, leading to the formation of potentially neurotoxic amyloid fibrils. During pathogenesis of prion disease, the prion protein misfolds into β-sheet rich, protease-resistant isoforms. A key, hydrophobic domain within the prion protein, comprising residues 109-122, recapitulates many properties of the full protein, such as helix-to-sheet structural transition, formation of fibrils and cytotoxicity of the misfolded isoform. Using all-atom, molecular simulations, it is demonstrated that the monomeric 109-122 peptide has a preference for α-helical conformations, but that this peptide can also form β-hairpin structures resulting from turns around specific glycine residues of the peptide. Altering a single amino acid within the 109-122 peptide (A117V, associated with familial prion disease) increases the prevalence of β-hairpin formation and these observations are replicated in a longer peptide, comprising residues 106-126. Multi-molecule simulations of aggregation yield different assemblies of peptide molecules composed of conformationally-distinct monomer units. Small molecular assemblies, consistent with oligomers, comprise peptide monomers in a β-hairpin-like conformation and in many simulations appear to exist only transiently. Conversely, larger assemblies are comprised of extended peptides in predominately antiparallel β-sheets and are stable relative to the length of the simulations. These larger assemblies are consistent with amyloid fibrils, show cross-β structure and can form through elongation of monomer units within pre-existing oligomers. In some simulations, assemblies containing both β-hairpin and linear peptides are evident. Thus, in this work oligomers are on pathway to fibril formation and a preference for β-hairpin structure should enhance oligomer formation whilst inhibiting maturation into fibrils. These simulations provide an important new atomic-level model for the formation of oligomers and fibrils of the prion protein and suggest that stabilization of β-hairpin structure may enhance cellular toxicity by altering the balance between oligomeric and fibrillar protein assemblies.

Dataset Information

β-Hairpin Alignment Alters Oligomer Formation in Aβ-Derived Peptides.

Publications

β-Hairpin Alignment Alters Oligomer Formation in Aβ-Derived Peptides.

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