PRION PROTEIN NMR STRUCTURE AND FAMILIAL HUMAN SPONGIFORM ENCEPHALOPATHIES

The refined NMR structure of the mouse prion protein domain mPrP(121-2 31) and the recently reported NMR structure of the complete 208-residu e polypeptide chain of mPrP are used to investigate the structural bas is of inherited human transmissible spongiform encephalopathies. In th e cellular form of mPrP no Spatial clustering of mutation sites is obs erved that would indicate the existence of disease-specific subdomains . A hydrogen bond between residues 128 and 178 provides a structural b asis for the observed highly specific influence of a polymorphism in p osition 129 in human PrP on the disease phenotype that segregates with the mutation Asp-178-Asn. Overall, the NMR structure implies that onl y part of the disease-related amino acid replacements lead to reduced stability of the cellular form of PrP, indicating that subtle structur al differences in the mutant proteins may affect intermolecular signal ing in a variety of different ways.