Contribution à l’étude des peptides obliques impliqués dans des transconformations

The study of the amyloidogenic proteins is important to understand the
transconformational processes. These proteins have a unique common feature : they undergo a
conformational change leading to the formation of highly structured fibrils that are mainly β
conformed. These proteins are difficult to study experimentally due to their low solubility and
their tendency to aggregate rapidly.
Recently, tilted peptides have been detected in such proteins. These peptides are short
fragments (11 to 18 residues) that adopt a tilted orientation when they interact with a
hydrophilic/hydrophobic interface. This property is due to the presence of an asymmetric
hydrophobicity gradient when they are helical. Those peptides are able to destabilize
organized molecular systems. Amyloidogenic proteins containing such peptides are the PrP
protein, the Aȕ peptide, and the bacterial prions Ure2p and Sup35p. The presence of such fragments in transconformational proteins has led to the
hypothesis that tilted peptides could be implied in the conformational change of
amyloidogenic proteins. These peptides could play a role through their destabilizing
properties and/or their structural lability.
The aim of this work was to detect tilted peptides among other amyloidogenic proteins
by molecular modelling. One of the detected peptides is tested experimentally to evidence its
lipid destabilizing properties. Five tilted peptides from four different proteins have been
detected among 27 amyloidogenic proteins. The tilted fragment from the α-synuclein
sequence, a protein involved in Parkinson disease, has been synthetized and tested for lipid
fusion. The fusogenic assays pointed out its destabilizing properties. These results support the
hypothesis that tilted peptides could be involved in transconformational processes.