Switch-peptides as folding precursors in self-assembling peptides and amyloid fibrillogenesis

Gabriele Tuchscherer, Arunan Chandravarkar, Marie Stéphanie Camus, Jérémy Bérard, Karine Murat, Adrian Schmid, Richard Mimna, Hilal A. Lashuel, Manfred Mutter

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

The study of conformational transitions of peptides has obtained considerable attention recently because of their importance as a molecular key event in a variety of degenerative diseases. However, the study of peptide self-assembly into β-sheets and amyloid β (Aβ) fibrils is strongly hampered by their difficult synthetic access and low solubility. We have recently developed a new concept termed "switch-peptides" that allows the controlled onset of polypeptide folding and misfolding at physiologic conditions. As a major feature, the folding process is initiated by chemically or enzyme triggered O,N-acyl migration in flexible and soluble folding precursors containing Ser- or Thr-derived switch (S)-elements. The elaborated methodologies are exemplified for the in situ conversion of NPY- and Cyclosporine A-derived prodrugs, as well as for the onset and reversal of α and β conformational transitions in Aβ peptides. In combining orthogonally addressable switch-elements, the consecutive switching on of S-elements gives new insights into the role of individual peptide segments ("hot spots") in early processes of polypeptide self-assembly and fibrillogenesis. Finally, the well-known secondary structure disrupting effect of pseudoprolines (ψPro) is explored for its use as a building block (S-element) in switch-peptides. To this end, synthetic strategies are described, allowing for the preparation of ψ Pro-containing folding precursors, exhibiting flexible random-coil conformations devoid of fibril forming propensity. The onset of β-sheet and fibril formation by restoring the native peptide chain in a single step classify ψ Pro-units as the most powerful tool for inhibiting peptide self-assembly, and complement the present methodologies of the switch-concept for the study of fibrillogenesis.

Original languageEnglish
Pages (from-to)239-252
Number of pages14
JournalBiopolymers - Peptide Science Section
Volume88
Issue number2
DOIs
Publication statusPublished - 2 May 2007
Externally publishedYes

Fingerprint

Amyloid
Peptides
Switches
Self assembly
Polypeptides
Prodrugs
Conformations
Enzymes
Solubility
Cyclosporine

Keywords

  • α-helix to β-sheet reversal
  • β-sheet disruption
  • Amyloid β fibrillogenesis
  • Conformational transitions
  • Enzyme-triggered O,N-acyl migration
  • Folding precursors
  • Pseudoprolines (ψ Pro)
  • Self-assembling peptides
  • Switch-peptides

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Biophysics

Cite this

Tuchscherer, G., Chandravarkar, A., Camus, M. S., Bérard, J., Murat, K., Schmid, A., ... Mutter, M. (2007). Switch-peptides as folding precursors in self-assembling peptides and amyloid fibrillogenesis. Biopolymers - Peptide Science Section, 88(2), 239-252. https://doi.org/10.1002/bip.20663

Switch-peptides as folding precursors in self-assembling peptides and amyloid fibrillogenesis. / Tuchscherer, Gabriele; Chandravarkar, Arunan; Camus, Marie Stéphanie; Bérard, Jérémy; Murat, Karine; Schmid, Adrian; Mimna, Richard; Lashuel, Hilal A.; Mutter, Manfred.

In: Biopolymers - Peptide Science Section, Vol. 88, No. 2, 02.05.2007, p. 239-252.

Research output: Contribution to journalArticle

Tuchscherer, G, Chandravarkar, A, Camus, MS, Bérard, J, Murat, K, Schmid, A, Mimna, R, Lashuel, HA & Mutter, M 2007, 'Switch-peptides as folding precursors in self-assembling peptides and amyloid fibrillogenesis', Biopolymers - Peptide Science Section, vol. 88, no. 2, pp. 239-252. https://doi.org/10.1002/bip.20663
Tuchscherer, Gabriele ; Chandravarkar, Arunan ; Camus, Marie Stéphanie ; Bérard, Jérémy ; Murat, Karine ; Schmid, Adrian ; Mimna, Richard ; Lashuel, Hilal A. ; Mutter, Manfred. / Switch-peptides as folding precursors in self-assembling peptides and amyloid fibrillogenesis. In: Biopolymers - Peptide Science Section. 2007 ; Vol. 88, No. 2. pp. 239-252.
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