Structure of the β2-α2 loop and interspecies prion transmission
Structure of the β2-α2 loop and interspecies prion transmission
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DOI：
10.1096/fj.11-200923
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发表时间：
2012-07-01
期刊：
影响因子：
4.8
通讯作者：
Sigurdson, Christina J.
中科院分区：
文献类型：
--
作者：
Bett, Cyrus;Fernandez-Borges, Natalia;Sigurdson, Christina J.
朊病毒是朊病毒蛋白的错误折叠、聚集的构象异构体，可以在物种之间传播。尽管传染性朊病毒和宿主朊病毒蛋白之间的结构相似性对于有效转化为错误折叠构象异构体是必需的，但种间传播的精确决定因素仍不清楚。内源性朊病毒蛋白 PrPC 的 β2-α2 环区域与朊病毒传播的障碍有关。我们最近发现，当传入的朊病毒蛋白和宿主朊病毒蛋白具有相似的 β 2-α 2 环结构时，转换是有效的；然而，一级结构同源性与二级结构同源性的作用无法区分。在这里，我们解开了β2-α2环的一级和二级结构同源性对朊病毒转化的影响。我们将来自具有无序或有序β2-α2环的动物的朊病毒接种到由于单残基取代(D167S)而具有无序环或有序环的小鼠中。我们发现朊病毒转化是由同源一级结构驱动的，并且独立于同源二级结构而发生。同样，使用来自具有无序或有序环的小鼠的 PrPC 和来自 5 个物种的朊病毒的无细胞转化与环的一级结构同源性相关，但与二级结构同源性无关。因此，我们的研究结果支持一个模型，其中有效的种间朊病毒转化是由初级序列的小片段决定的，而不是由 PrP.-Bett, C.、Fernandez-Borges, N.、Kurt, T. D.、Lucero, M.、Nilsson, K. P. R.、Castilla, J.、Sigurdson, C. J. 的二级结构决定的。β 2-α 2 环的结构和种间朊病毒传播。 FASEB J. 26, 2868-2876 (2012)。 www.fasebj.org
Prions are misfolded, aggregated conformers of the prion protein that can be transmitted between species. The precise determinants of interspecies transmission remain unclear, although structural similarity between the infectious prion and host prion protein is required for efficient conversion to the misfolded conformer. The beta 2-alpha 2 loop region of endogenous prion protein, PrPC, has been implicated in barriers to prion transmission. We recently discovered that conversion was efficient when incoming and host prion proteins had similar beta 2-alpha 2 loop structures; however, the roles of primary vs. secondary structural homology could not be distinguished. Here we uncouple the effect of primary and secondary structural homology of the beta 2-alpha 2 loop on prion conversion. We inoculated prions from animals having a disordered or an ordered beta 2-alpha 2 loop into mice having a disordered loop or an ordered loop due to a single residue substitution (D167S). We found that prion conversion was driven by a homologous primary structure and occurred independently of a homologous secondary structure. Similarly, cell-free conversion using PrPC from mice with disordered or ordered loops and prions from 5 species correlated with primary but not secondary structural homology of the loop. Thus, our findings support a model in which efficient interspecies prion conversion is determined by small stretches of the primary sequence rather than the secondary structure of PrP.-Bett, C., Fernandez-Borges, N., Kurt, T. D., Lucero, M., Nilsson, K. P. R., Castilla, J., Sigurdson, C. J. Structure of the beta 2-alpha 2 loop and interspecies prion transmission. FASEB J. 26, 2868-2876 (2012). www.fasebj.org