Induction of β-sheet structure in amyloidogenic peptides by neutralization of aspartate: A model for amyloid nucleation

Jozef Orpiszewski, Merrill Benson

Research output: Contribution to journalArticle

43 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)413-428
Number of pages16
JournalJournal of Molecular Biology
Volume289
Issue number2
DOIs
StatePublished - Jun 4 1999

Fingerprint

Amyloidogenic Proteins
Amyloid
Aspartic Acid
Peptides
Esters
Serum Amyloid A Protein
Amyloidosis
Cyclization
Circular Dichroism
Amides
Solubility
Glutamic Acid

Keywords

  • β-hairpin
  • β-sheet
  • Alzheimer disease
  • Amyloid nucleation
  • Post-translational modification

ASJC Scopus subject areas

  • Virology

Cite this

Induction of β-sheet structure in amyloidogenic peptides by neutralization of aspartate : A model for amyloid nucleation. / Orpiszewski, Jozef; Benson, Merrill.

In: Journal of Molecular Biology, Vol. 289, No. 2, 04.06.1999, p. 413-428.

Research output: Contribution to journalArticle

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