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.

可溶性病毒蛋白会偶然遇到外来病毒聚集体，从而导致跨物种的病毒传播。然而，如何通过宿主可溶性病毒蛋白的结构波动来调节其效率仍未解决。在本研究中，通过使用两个远缘相关的酵母病毒Sup35蛋白，我们发现短无序节段的特定构型控制着种间病毒的可传播性。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，这些残基通过局部改变动力学和可溶性soluble病毒蛋白的构象，允许种间病毒在体内和体外传播。值得注意的是 由天冬酰胺和谷氨酰胺之间的亚甲基引起的微妙的构象差异足以改变短链段结构并基本上调节交叉播种活性。因此，我们的发现揭示了宿主病毒蛋白中短片段的构象动力学如何影响跨物种的ion病毒传播。更广泛地讲，我们的研究为异源蛋白之间的交叉播种提供了机械方面的见识。