Analytical background and discussion of the chaperone model of prion diseases

It is generally accepted that prion infection is due solely to a protein i. e. the protein-only hypothesis. The essential constituent of infectious pri ons is the scrapie prion Protein (PrPSc) which is chemically indistinguisha ble from the normal, cellular protein (PrPC) but exhibits distinct secondar y and tertiary structure. This very unusual feature seems to be in contradi ction with a major paradigm of present structural biology stated by Anfinse n: a protein folds to the most stable conformation, this means only one str ucture. In order to reconcile the results obtained on prions with the biophysics of protein folding, a model is proposed. It is based on the hypothesis that a thermodynamically irreversible step is involved in protein folding. The mo del is then extended to chaperone-assisted protein folding. It is shown tha t, under certain conditions, the transitory secondary structure formed duri ng the earlier step of folding could interact with chaperone. Analysis show s that chaperone may help the protein to find correct conformation. On the other hand, analysis reveals the possibility that more than one structure m ay form from a single polypeptide chain. Under these conditions, the behavi our of chaperones resembles the characteristics of prion diseases.