Short disordered protein segment regulates cross-species transmission of a yeast prion
Short disordered protein segment regulates cross-species transmission of a yeast prion
复制标题
短无序蛋白片段调节酵母朊病毒的跨物种传播
DOI：
10.1038/s41589-020-0516-y
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发表时间：
2020
期刊：
影响因子：
14.8
通讯作者：
Tanaka M.
中科院分区：
文献类型：
--
作者：
Shida T;Kamatari YO;Yoda T;Yamaguchi Y;Feig M;Ohhashi Y;Sugita Y;Kuwata K;Tanaka M.
可溶性的普恩蛋白偶然遇到外来的普恩聚集体，导致普恩跨物种传播。然而，宿主可溶性蛋白的结构波动是如何调节其效率的，目前还没有解决。在本研究中，通过使用两个远缘关系较远的酵母Pron Sup35蛋白，我们发现一段短的无序片段的特定构象控制着Prion的种间传递性。利用包括高分辨率核磁共振和分子动力学模拟在内的多学科方法，我们通过局部改变可溶病毒蛋白的动态和构象，确定了该片段中的关键残基，这些残基允许在体外和体内进行种间病毒传播。值得注意的是，天冬酰胺和谷氨酰胺之间由亚甲基引起的微小构象差异足以改变短片段结构，并实质上调节交叉种子的活性。因此，我们的发现揭示了宿主Prion蛋白中短片段的构象动力学如何影响Prion的跨物种传播。更广泛地说，我们的研究为异源蛋白质之间的交叉播种提供了机械性的见解。
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.