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

• Published in: Biopolymers Vol. 88; no. 2; pp. 239 - 252
• Main Authors: Tuchscherer, Gabriele, Chandravarkar, Arunan, Camus, Marie-Stéphanie, Bérard, Jérémy, Murat, Karine, Schmid, Adrian, Mimna, Richard, Lashuel, Hilal A., Mutter, Manfred
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 2007
• Subjects: Amyloid - chemistry; Amyloid - ultrastructure; amyloid β fibrillogenesis; conformational transitions; enzyme-triggered O; enzyme‐triggered O,N‐acyl migration; folding precursors; Microscopy, Electron; Models, Biological; Models, Molecular; N-acyl migration; Peptides - chemistry; Proline - analogs & derivatives; Proline - chemistry; Protein Folding; Protein Precursors - chemistry; Protein Precursors - ultrastructure; Protein Structure, Secondary; pseudoprolines (ΨPro); self-assembling peptides; switch-peptides; Thiazoles - chemistry; α-helix to β-sheet reversal; β-sheet disruption
• DOI: 10.1002/bip.20663
• EISSN: 1097-0282
• ISSN: 0006-3525

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 selfassembly 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. © 2007 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 88: 239–252, 2007.
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