Induction of β-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 β-sheet secondary structure and similar tertiary structure. While some amyloidogenic proteins are rich in β-sheet in their soluble form, others, like Alzheimer β-amyloid peptide (Aβ) or serum amyloid A, must undergo significant structural transition to acquire a high β-sheet content. We postulate that Aβ and other amyloidogenic proteins undergo a transition to β-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 β-sheet content at neutral and basic pH. A higher content of β-sheet structure correlated with increased propensity for fibril formation and decreased solubility at neutral pH.