Soluble prion proteins contingently encounter foreign prion aggregates, leading to cross-species prion transmission. However, how its efficiency is regulated by structural fluctuation of the host soluble prion protein remains unsolved. In the present study, through the use of two distantly related yeast prion Sup35 proteins, we found that a specific conformation of a short disordered segment governs interspecies prion transmissibility. Using a multidisciplinary approach including high-resolution NMR and molecular dynamics simulation, we identified critical residues within this segment that allow interspecies prion transmission in vitro and in vivo, by locally altering dynamics and conformation of soluble prion proteins. Remarkably, subtle conformational differences caused by a methylene group between asparagine and glutamine sufficed to change the short segment structure and substantially modulate the cross-seeding activity. Thus, our findings uncover how conformational dynamics of the short segment in the host prion protein impacts cross-species prion transmission. More broadly, our study provides mechanistic insights into cross-seeding between heterologous proteins.
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We thank N. Takahashi for reagent preparation, H. Chih-Hao Shen for advice on NMR analysis, H. Kurahashi for advice on yeast experiments and the members of Tanaka laboratory for discussion. DNA-sequencing and MS were performed by the RIKEN Center for Brain Science Research Resources Division. Funding was provided by the Grants-in-Aid for Scientific Research (B) (no. 15H04345; to M.T.) from the Ministry of Education, Culture, Sports, Science and Technology, Japan, the Grants-in-Aid for the Research Committee of Prion Disease and Slow Virus Infection (to Y.O., K.K. and M.T.) from the Ministry of Health, Labour and Welfare, Japan. M.T. received funding from the following: the RIKEN Pioneering Project (Cellular Evolution), the RIKEN Aging Project, Takeda Science Foundation, Nakatani Foundation, the Kato Memorial Trust for Nambyo Research and the Mochida Foundation. T.S. was a recipient of the Junior Research Associate fellowship from RIKEN.
The authors declare no competing interests.
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Shida, T., Kamatari, Y.O., Yoda, T. et al. Short disordered protein segment regulates cross-species transmission of a yeast prion. Nat Chem Biol 16, 756–765 (2020). https://doi.org/10.1038/s41589-020-0516-y
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