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NMR structure of the mouse prion protein domain PrP(121-231)
1Institut für Molekularbiologie und Biophysik, Eidgenossische Technische Hochschule-Honggerberg, Zürich, Switzerland.
Abstract:
The 'protein only' hypothesis 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. Prion proteins are thought to exist in two different conformations: the 'benign' PrPcform, and the infectious 'scrapie form', PrPsc. Knowledge of the three-dimensional structure of PrPc is essential for understanding the transition to PrPsc. The nuclear magnetic resonance (NMR) structure of the autonomously folding PrP domain comprising residues 121-231 (ref. 6) contains a two-stranded antiparallel beta-sheet and three alpha-helices. This domain contains most of the point-mutation sites that have been linked, in human PrP, to the occurrence of familial prion diseases. The NMR structure shows that these mutations occur within, or directly adjacent to, regular secondary structures. The presence of a beta-sheet in PrP(121-231) is in contrast with model predictions of an all-helical structure of PrPc (ref. 8), and may be important for the initiation of the transition from PrPc to PrPsc.
Insights
The prion protein hypothesis suggests a misfolded prion protein (PrPsc) causes neurodegenerative diseases. Understanding the normal prion protein
Area of Science:
- Neuroscience
- Structural Biology
- Biochemistry
Background:
- The 'protein only' hypothesis posits that a misfolded prion protein (PrPsc) induces neurodegenerative diseases like BSE and CJD.
- Prion proteins exist in normal (PrPc) and infectious (PrPsc) forms, with structural knowledge crucial for understanding the PrPc to PrPsc transition.
Purpose of the Study:
- To determine the three-dimensional structure of the autonomously folding prion protein (PrP) domain (residues 121-231).
- To investigate the structural basis of familial prion diseases linked to mutations within this PrP domain.
Main Methods:
- Nuclear Magnetic Resonance (NMR) spectroscopy was used to elucidate the structure of the PrP(121-231) domain.
Main Results:
- The NMR structure revealed a two-stranded antiparallel beta-sheet and three alpha-helices within the PrP(121-231) domain.
- Identified that disease-associated mutations cluster within or near these secondary structures.
- The presence of a beta-sheet contradicts previous all-helical predictions for PrPc.
Conclusions:
- The determined PrP(121-231) structure provides insights into the normal prion protein conformation.
- The structural findings, particularly the beta-sheet, may be critical for understanding the mechanism of PrPc conversion to PrPsc.
- This structural information is vital for comprehending the etiology of familial prion diseases.