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 different conformations 5 : the 'benign' PrP C form, and the infectious 'scrapie form', PrP Sc . Knowledge of the three-dimensional structure of PrP C is essential for understanding the transition to PrP Sc . The nuclear magnetic resonance (NMR) structure of the autonomously folding PrP domain comprising residues 121–231 (ref. 6) contains a two-stranded anti-parallel β-sheet and three α-helices. This domain contains most of the point-mutation sites that have been linked, in human PrP, to the occurrence of familial prion diseases 7 . The NMR structure shows that these mutations occur within, or directly adjacent to, regular secondary structures. The presence of a β-sheet in PrP(121–231) is in contrast with model predictions of an all-helical structure of PrP C (ref. 8), and may be important for the initiation of the transition from PrP C to PrP Sc .