Switch-peptides as folding precursors in self-assembling peptides and amyloid fibrillogenesis.
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 beta-sheets and amyloid beta (Abeta) 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 alpha and beta conformational transitions in Abeta 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 (PsiPro) 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 PsiPro-containing folding precursors, exhibiting flexible random-coil conformations devoid of fibril forming propensity. The onset of beta-sheet and fibril formation by restoring the native peptide chain in a single step classify PsiPro-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.
Tuchscherer
Gabriele
G
Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, EPFL, CH-1015 Lausanne, Switzerland.
Chandravarkar
Arunan
A
Camus
Marie-Stéphanie
MS
Bérard
Jérémy
J
Murat
Karine
K
Schmid
Adrian
A
Mimna
Richard
R
Lashuel
Hilal A
HA
Mutter
Manfred
M
D000682:Amyloid / Q000737:chemistry* / Q000648:ultrastructure; D008854:Microscopy, Electron; D008954:Models, Biological; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry*; D011392:Proline / Q000031:analogs & derivatives / Q000737:chemistry; D017510:Protein Folding; D011498:Protein Precursors / Q000737:chemistry / Q000648:ultrastructure; D017433:Protein Structure, Secondary; D013844:Thiazoles / Q000737:chemistry
D000682:Amyloid; D010455:Peptides; D011498:Protein Precursors; D013844:Thiazoles; C505976:pseudoproline; D011392:Proline