title: Induction of beta-sheet structure in amyloidogenic peptides by neutralization of aspartate: a model for amyloid nucleation.
abstract: Amyloid fibril formation is widely accepted as a critical step in all types of amyloidosis. Amyloid fibrils derived from different amyloidogenic proteins share structural elements including beta-sheet secondary structure and similar tertiary structure. While some amyloidogenic proteins are rich in beta-sheet in their soluble form, others, like Alzheimer beta-amyloid peptide (Abeta) or serum amyloid A, must undergo significant structural transition to acquire a high beta-sheet content. We postulate that Abeta and other amyloidogenic proteins undergo a transition to beta-sheet as a result of aging-related chemical modifications of aspartyl residues to the form of succinimide or isoaspartyl methyl ester. We hypothesize that spontaneous cyclization of aspartate residues in amyloidogenic proteins can serve as a nucleation event in amyloidogenesis. To test this hypothesis, we synthesized a series of designed peptides having the sequence VTVKVXAVKVTV, where X represents aspartic acid or its derivatives. Studies using circular dichroism showed that neutralization of the aspartate residue through the formation of a methyl ester or an amide, or replacement of aspartate with glutamate led to an increased beta-sheet content at neutral and basic pH. A higher content of beta-sheet structure correlated with increased propensity for fibril formation and decreased solubility at neutral pH.
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
authors.forename: J
authors.initials: J
authors.lastname: Orpiszewski
authors.forename: M D
authors.initials: MD
authors.lastname: Benson
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000648:ultrastructure; D000686:Amyloidosis / Q000235:genetics; D001224:Aspartic Acid; D002942:Circular Dichroism; D004355:Drug Stability; D018260:Gelsolin / Q000737:chemistry; D006801:Humans; D008854:Microscopy, Electron; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry* / Q000648:ultrastructure; D017354:Point Mutation; D011228:Prealbumin / Q000737:chemistry; D011328:Prions / Q000737:chemistry; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D016229:Amyloid beta-Peptides; D018260:Gelsolin; D009842:Oligopeptides; D010446:Peptide Fragments; D011228:Prealbumin; D011328:Prions; D001224:Aspartic Acid