NMR STRUCTURE OF THE MOUSE PRION PROTEIN DOMAIN PRP(121-231)

THE 'protein only' hypothesis(1) states that a modified form of normal prion protein triggers infectious neurodegenerative diseases, such as bovine spongiform encephalopathy (BSE), or Creutzfeldt-Jakob disease (CJD) in humans(2-4). Prion proteins are thought to exist in two diffe rent conformations(5): the 'benign' PrPC form, and the infections 'scr apie form', PrPSc. Knowledge of the three-dimensional structure of PrP C is essential for understanding the transition to PrPSc. The nuclear magnetic resonance (NMR) structure of the autonomously folding PrP dom ain comprising residues 121-231 (ref. 6) contains a two-stranded antip arallel beta-sheet and three alpha-helices. This domain contains most of the point-mutation sites that have been linked, in human PrP, to th e occurrence of familial prion diseases(7). The NMR structure shows th at these mutations occur within, or directly adjacent to, regular seco ndary structures, The presence of a beta-sheet in PrP(121-231) is in c ontrast with model predictions of an all-helical structure of PrPC (re f. 8), and may be important for the initiation of the transition from PrPC to PrPSc.