Polymorphism at residue 129 modulates the conformational conversion of the D178N variant of human prion protein 90-231.

One of the arguments in favor of the protein-only hypothesis of transmissible spongiform encephalopathies is the link between inherited prion diseases and specific mutations in the PRNP gene. One such mutation (Asp178 --> Asn) is associated with two distinct disorders: fatal familial insomnia or familial Creutzfeldt-Jakob disease, depending upon the presence of Met or Val at position 129, respectively. In this study, we have characterized the biophysical properties of recombinant human prion proteins (huPrP90-231) corresponding to the polymorphic variants D178N/M129 and D178N/V129.

Molecular basis of barriers for interspecies transmissibility of mammalian prions.

Spongiform encephalopathies are believed to be transmitted by a unique mechanism involving self-propagating conformational conversion of prion protein into a misfolded form. Here we demonstrate that fundamental aspects of mammalian prion propagation, including the species barrier and strain diversity, can be reproduced in vitro in a seeded fibrillization of the recombinant prion protein variant Y145Stop. Our data show that species-specific substitution of a single amino acid in a critical region completely changes the seeding specificity of prion protein fibrils.

Nucleation-dependent conformational conversion of the Y145Stop variant of human prion protein: structural clues for prion propagation.

One of the most intriguing disease-related mutations in human prion protein (PrP) is the Tyr to Stop codon substitution at position 145. This mutation results in a Gerstmann-Straussler-Scheinker-like disease with extensive PrP amyloid deposits in the brain. Here, we provide evidence for a spontaneous conversion of the recombinant polypeptide corresponding to the Y145Stop variant (huPrP23-144) from a monomeric unordered state to a fibrillar form.

Disease-associated F198S mutation increases the propensity of the recombinant prion protein for conformational conversion to scrapie-like form.

The critical step in the pathogenesis of transmissible spongiform encephalopathies (prion diseases) is the conversion of a cellular prion protein (PrP(c)) into a protease-resistant, beta-sheet rich form (PrP(Sc)). Although the disease transmission normally requires direct interaction between exogenous PrP(Sc) and endogenous PrP(C), the pathogenic process in hereditary prion diseases appears to develop spontaneously (i.e.