NR AJBK
AU Orpiszewski,J.; Benson,M.D.
TI Induction of beta-sheet structure in amyloidogenic peptides by neutralization of aspartate: a model for amyloid nucleation.
QU Journal of Molecular Biology 1999 Jun 4; 289(2): 413-28
PT journal article
AB 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.
MH Amino Acid Sequence; Amino Acid Substitution; Amyloid beta-Protein/*chemistry/ultrastructure; Amyloidosis/genetics; *Aspartic Acid; Circular Dichroism; Drug Stability; Gelsolin/chemistry; Human; Microscopy, Electron; Oligopeptides/chemical synthesis/chemistry; Peptide Fragments/chemical synthesis/*chemistry/ultrastructure; Point Mutation; Prealbumin/chemistry; Prions/chemistry; *Protein Structure, Secondary; Protein Structure, Tertiary
AD Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
SP englisch
PO England