Evaluating Prion Models Based on Comprehensive Mutation Data of Mouse PrP

• Published in: Structure (London) 2014-04, Vol.22 (4), p.560-571
• Main Authors: Shirai, Tsuyoshi, Saito, Mihoko, Kobayashi, Atsushi, Asano, Masahiro, Hizume, Masaki, Ikeda, Shino, Teruya, Kenta, Morita, Masanori, Kitamoto, Tetsuyuki
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Amino acids; Animals; Cell Line, Tumor; Compatibility; Conversion; Gene Expression; Knowledge base; Mice; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; Mutations; Neurons - cytology; Neurons - metabolism; Point Mutation; Prions; Protein Structure, Secondary; Protein Structure, Tertiary; Proteins; PrPSc Proteins - chemistry; PrPSc Proteins - genetics; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Summaries; Transfection
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2013.12.019

The structural details of the essential entity of prion disease, fibril prion protein (PrPSc), are still elusive despite the large body of evidence supporting the prion hypothesis. Five major working models of PrPSc structure, which are not compatible with each other, have been proposed. However, no systematic evaluation has been performed on those models. We devised a method that combined systematic point mutation with threading on knowledge-based amino acid potentials. A comprehensive mutation experiment was performed on mouse prion protein, and the PrPSc conversion efficiency of each mutant was examined. The models were evaluated based on the mutation data by using the threading method. Although the data turned out to be rather more consistent with the models that assumed a conversion of the N-terminal region of core PrP into a β helix than with others, substantial modifications were also required to further improve the current model based on recent experimental results. [Display omitted] •A comprehensive mutational study of core region of mouse PrP was executed•The results revealed importance of the N-terminal region for PrPSc conversions•An integrated evaluation of proposed PrPSc models was done based on mutation data•A revised PrPSc model that better explained experimental data was proposed in this study Shirai et al. perform a comprehensive mutation experiment on mouse prion protein PrP and apply a method that combined systematic point mutation with threading on knowledge-based amino acid potentials to evaluate structural models of PrPSc. This leads to a proposal that the current model needs to be revised.