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Polymorphism of oligomers of a peptide from ?-amyloid.

ABSTRACT: This contribution reports solution-phase structural studies of oligomers of a family of peptides derived from the ?-amyloid peptide (A?). We had previously reported the X-ray crystallographic structures of the oligomers and oligomer assemblies formed in the solid state by a macrocyclic ?-sheet peptide containing the A?(15-23) nonapeptide. In the current study, we set out to determine its assembly in aqueous solution. In the solid state, macrocyclic ?-sheet peptide 1 assembles to form hydrogen-bonded dimers that further assemble in a sandwich-like fashion to form tetramers through hydrophobic interactions between the faces bearing V18 and F20. In aqueous solution, macrocyclic ?-sheet peptide 1 and homologue 2a form hydrogen-bonded dimers that assemble to form tetramers through hydrophobic interactions between the faces bearing L17, F19, and A21. In the solid state, the hydrogen-bonded dimers are antiparallel, and the ?-strands are fully aligned, with residues 17-23 of one of the macrocycles aligned with residues 23-17 of the other. In solution, residues 17-23 of the hydrogen-bonded dimers are shifted out of alignment by two residues toward the C-termini. The two hydrogen-bonded dimers are nearly orthogonal in the solid state, while in solution the dimers are only slightly rotated. The differing morphology of the solution-state and solid-state tetramers is significant, because it may provide a glimpse into some of the structural bases for polymorphism among A? oligomers in Alzheimer's disease.

SUBMITTER: Pham JD

PROVIDER: S-EPMC4004211 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Polymorphism of oligomers of a peptide from β-amyloid.

Pham Johnny D JD Demeler Borries B Nowick James S JS

Journal of the American Chemical Society 20140326 14

This contribution reports solution-phase structural studies of oligomers of a family of peptides derived from the β-amyloid peptide (Aβ). We had previously reported the X-ray crystallographic structures of the oligomers and oligomer assemblies formed in the solid state by a macrocyclic β-sheet peptide containing the Aβ(15-23) nonapeptide. In the current study, we set out to determine its assembly in aqueous solution. In the solid state, macrocyclic β-sheet peptide 1 assembles to form hydrogen-bo ...[more]

PMID: 24669785

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Project description:Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the pathological aggregation of the amyloid-? peptide (A?). Monomeric soluble A? can switch from helicoidal to ?-sheet conformation, promoting its assembly into oligomers and subsequently to amyloid fibrils. Oligomers are highly toxic to neurons and have been reported to induce synaptic transmission impairments. The progression from oligomers to fibrils forming senile plaques is currently considered a protective mechanism to avoid the presence of the highly toxic oligomers. Protein nitration is a frequent post-translational modification under AD nitrative stress conditions. A? can be nitrated at tyrosine 10 (Y10) by peroxynitrite. Based on our analysis of ThT binding, Western blot and electron and atomic force microscopy, we report that A? nitration stabilizes soluble, highly toxic oligomers and impairs the formation of fibrils. We propose a mechanism by which fibril elongation is interrupted upon Y10 nitration: Nitration disrupts fibril-forming folds by preventing H14-mediated bridging, as shown with an A? analog containing a single residue (H to E) replacement that mimics the behavior of nitrated A? related to fibril formation and neuronal toxicity. The pathophysiological role of our findings in AD was highlighted by the study of these nitrated oligomers on mouse hippocampal neurons, where an increased NMDAR-dependent toxicity of nitrated A? oligomers was observed. Our results show that A? nitrotyrosination is a post-translational modification that increases A? synaptotoxicity. SIGNIFICANCE STATEMENT:We report that nitration (i.e., the irreversible addition of a nitro group) of the Alzheimer-related peptide amyloid-? (A?) favors the stabilization of highly toxic oligomers and inhibits the formation of A? fibrils. The nitrated A? oligomers are more toxic to neurons due to increased cytosolic calcium levels throughout their action on NMDA receptors. Sustained elevated calcium levels trigger excitotoxicity, a characteristic event in Alzheimer's disease.

Dataset Information

Polymorphism of oligomers of a peptide from ?-amyloid.

Publications

Polymorphism of oligomers of a peptide from β-amyloid.

Similar Datasets

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