SPECTROSCOPIC CHARACTERIZATION OF CONFORMATIONAL DIFFERENCES BETWEEN PRPC AND PRPSC - AN ALPHA-HELIX TO BETA-SHEET TRANSITION

Although no chemical modifications have been found to distinguish the cellular prion protein PrPC from its infectious analogue PrPSc, spectr oscopic methods such as Fourier transform infrared (FTIR) spectroscopy reveal a major conformational difference. PrPC is rich in alpha-helix but is devoid of beta-sheet, whereas PrPSc is high in beta-sheet. N-t erminal truncation of PrPSc by limited proteolysis does not destroy in fectivity but it increases the beta-sheet content and shifts the FTIR absorption to lower frequencies, typical of the cross beta-pleated she ets of amyloids. Thus the formation of PrPSc from PrPC involves a conf ormational transition in which one or more alpha-helical regions of th e protein is converted to beta-sheet. This transition is mimicked by s ynthetic peptides, allowing predictions of domains of PrP involved in prion diseases.