Ion-specific effects on prion nucleation and strain formation.
Ion-specific effects on prion nucleation and strain formation.
复制标题
对朊病毒成核和菌株形成的离子特异性影响。
DOI：
10.1074/jbc.m113.467829
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Bommarius,AndreasS
中科院分区：
文献类型：
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作者：
Rubin,Jonathan;Khosravi,Hasan;Bruce,KathrynL;Lydon,MeganE;Behrens,SvenH;Chernoff,YuryO;Bommarius,AndreasS
被称为淀粉样蛋白的错误折叠蛋白质的有序、纤维状、自我播种的聚集体与哺乳动物的重要疾病有关，并控制真菌的表型特征。一种给定的蛋白质可能采用多种淀粉样蛋白构象，称为变种或菌株，每一种都会导致一种不同的疾病模式或表型。在这里，我们研究了Hofmeister离子对酵母蛋白Sup35p的含有Prion结构域片段(Sup35 NM)的淀粉样蛋白成核和菌株产生的影响。水合较强的阴离子(Kosmotrope)迅速启动成核，导致纤维快速伸长，而水合较差的阴离子(Chotrope)延迟成核，对伸长率影响较小。我们首次证明，与混浊的淀粉样蛋白相比，高渗红细胞有利于淀粉样蛋白菌株的形成，其特征是热稳定性较低，体外脆性较高，在体内有效地具有较强的表型和增殖模式。这些现象表明霍夫迈斯特离子在生物化学上的内在差异。我们的工作表明，溶液的离子组成不仅影响淀粉样蛋白成核的动力学，而且决定优先形成的淀粉样蛋白应变。背景：Pron蛋白可能采用多个聚集体构象，称为应变。结果：全亲和杂致阴离子对聚集动力学有相反的影响，并有利于不同的应变。结论：Pron成核动力学和主导应变模式强烈依赖于聚集体混合物的离子组成。意义：离子组成被证明是Pron菌株产生的关键决定因素。
Ordered, fibrous, self-seeding aggregates of misfolded proteins known as amyloids are associated with important diseases in mammals and control phenotypic traits in fungi. A given protein may adopt multiple amyloid conformations, known as variants or strains, each of which leads to a distinct disease pattern or phenotype. Here, we study the effect of Hofmeister ions on amyloid nucleation and strain generation by the prion domain-containing fragment (Sup35NM) of a yeast protein Sup35p. Strongly hydrated anions (kosmotropes) initiate nucleation quickly and cause rapid fiber elongation, whereas poorly hydrated anions (chaotropes) delay nucleation and mildly affect the elongation rate. For the first time, we demonstrate that kosmotropes favor formation of amyloid strains that are characterized by lower thermostability and higher frangibilityin vitroand stronger phenotypic and proliferation patterns effectivelyin vivoas compared with amyloids formed in chaotropes. These phenomena point to inherent differences in the biochemistry of Hofmeister ions. Our work shows that the ionic composition of a solution not only influences the kinetics of amyloid nucleation but also determines the amyloid strain that is preferentially formed.Background: Prion proteins may adopt multiple aggregate conformations, known as strains.Results: Kosmotropic and chaotropic anions exhibit opposite effects on aggregation kinetics and favor different strains.Conclusion: Both prion nucleation kinetics and prevailing strain patterns strongly depend on ionic composition of the aggregation mixture.Significance: Ionic composition is shown to be a critical determinant in the generation of prion strains.