Implication of a structural motif in the instability of a toxic protein: the prion

Transmissible spongiform encephalopathies (TSE’s) are neurodegenerative diseases found in animals as well as in men. They are due to infection by non conventional transmission agents called «prions» The protein only hypothesis stipulates that the agent of the prion diseases is the PrPsc protein found in the inoculum. The sequence of this protein is strictly identical to a normal protein called PrPc. The only difference between PrPsc and PrPc is in the conformation: while the latter is mainly helical, the b;-sheet content is significantly increased in PrPsc, with a concomitant loss ofhelical structure. It is postulated that the disease is due to a structural conversion PrPc g; PrPsc induced by PrPsc present in the infectious fractions. By molecular modelling, we detected a so-called “tilted peptide” in the PrP sequence. Those short fragments have destabilizing properties, due to an asymmetric distribution of their hydrophobicity when helical. They were initially found in viral fusion proteins and later in series of proteins with various functions. Tilted peptides were shown to be structurally labile, their conformation depending upon the environment. We postulate that the PrP tilted fragment could be involved in the PrP neurotoxicity, and more generally, that tilted peptides could activate misfolding processes.