Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan.
Laboratory for Protein Conformation Diseases, RIKEN Center for Brain Science, Wako, Japan.
Nat Chem Biol. 2020 Jul;16(7):756-765. doi: 10.1038/s41589-020-0516-y. Epub 2020 Apr 13.
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.
可溶性朊病毒蛋白偶然遇到外来朊病毒聚集体，导致跨物种朊病毒传播。然而，其效率如何受到宿主可溶性朊病毒蛋白结构波动的调节仍未解决。在本研究中，我们通过使用两种亲缘关系较远的酵母朊病毒 Sup35 蛋白，发现短的无序片段的特定构象控制着种间朊病毒的传染性。通过使用包括高分辨率 NMR 和分子动力学模拟在内的多学科方法，我们确定了该片段内的关键残基，这些残基允许在体外和体内进行种间朊病毒的传播，方法是局部改变可溶性朊病毒蛋白的动力学和构象。值得注意的是，由于天冬酰胺和谷氨酰胺之间的亚甲基引起的细微构象差异足以改变短片段结构，并显著调节交叉接种活性。因此，我们的发现揭示了宿主朊病毒蛋白中短片段的构象动力学如何影响跨物种朊病毒的传播。更广泛地说，我们的研究为异源蛋白之间的交叉接种提供了机制上的见解。
