Influence of amino acid substitutions related to inherited human prion diseases on the thermodynamic stability of the cellular prion protein.

摘要: Transmissible spongiform encephalopathies (TSEs) are caused by a unique infectious agent which appears to be identical with PrPSc, an oligomeric, misfolded isoform of the cellular prion protein, PrPC. All inherited forms human TSEs, i.e., familial Creutzfeldt−Jakob disease, Gerstmann−Straussler−Scheinker syndrome, and fatal insomnia, segregate specific point mutations or insertions in gene coding for PrP. Here we have tested hypothesis that these destabilize PrPC thus facilitate its conversion into PrPSc. Eight disease-specific amino acid replacements located C-terminal domain PrPC, PrP(121−231), constitutes only part defined tertiary structure. Introduction all PrP(121−231) yielded variants same spectroscopic characteristics as wild-type similar full-length PrP(23−231), excludes possibility exchanges priori induce PrPSc-like conformation...