Prion protein NMR structure and familial human spongiform encephalopathies

Abstract

The refined NMR structure of the mouse prion protein domain m PrP(121–231) and the recently reported NMR structure of the complete 208-residue polypeptide chain of m PrP are used to investigate the structural basis of inherited human transmissible spongiform encephalopathies. In the cellular form of m PrP 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.