Proc Natl Acad Sci U S A 1998 Sep 29;95(20):11667-72

Prion protein NMR structure and familial human spongiform encephalopathies.

Riek R, Wider G, Billeter M, Hornemann S, Glockshuber R, Wuthrich K

Institut fur Molekularbiologie und Biophysik, Eidgenossische Technische Hochschule-Honggerberg, CH-8093 Zurich, Switzerland.

The refined NMR structure of the mouse prion protein domain mPrP(121-231) and the recently reported NMR structure of the complete 208-residue polypeptide chain of mPrP are used to investigate the structural basis of inherited human transmissible spongiform encephalopathies. In the cellular form of mPrP no spatial clustering of mutation sites is observed that would indicate the existence of disease-specific subdomains. A hydrogen bond between residues 128 and 178 provides a structural basis for the observed highly specific influence of a polymorphism in position 129 in human PrP on the disease phenotype that segregates with the mutation Asp-178-Asn. Overall, the NMR structure implies that only part of the disease-related amino acid replacements lead to reduced stability of the cellular form of PrP, indicating that subtle structural differences in the mutant proteins may affect intermolecular signaling in a variety of different ways.
 

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