Chen Buxin, Newnam Gary P, Chernoff Yury O
School of Biology and Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 310 Ferst Drive, Atlanta, GA 30332-0230, USA.
Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2791-6. doi: 10.1073/pnas.0611158104. Epub 2007 Feb 12.
Prions are self-perpetuating and, in most cases, aggregation-prone protein isoforms that transmit neurodegenerative diseases in mammals and control heritable traits in yeast. Prion conversion requires a very high level of identity of the interacting protein sequences. Decreased transmission of the prion state between divergent proteins is termed "species barrier" and was thought to occur because of the inability of divergent prion proteins to coaggregate. Species barrier can be overcome in cross-species infections, e.g., from "mad cows" to humans. We studied the counterparts of yeast prion protein Sup35, originated from three different species of the Saccharomyces sensu stricto group and exhibiting the range of prion domain divergence that overlaps with the range of divergence observed among distant mammalian species. All three proteins were capable of forming a prion in Saccharomyces cerevisiae, although prions formed by heterologous proteins were usually less stable than the endogenous S. cerevisiae prion. Heterologous Sup35 proteins coaggregated in the S. cerevisiae cells. However, in vivo cross-species prion conversion was decreased and in vitro polymerization was cross-inhibited in at least some heterologous combinations, thus demonstrating the existence of prion species barrier. Moreover, the barrier between the S. cerevisiae protein and its Saccharomyces paradoxus and Saccharomyces bayanus counterparts was asymmetric both in vivo and in vitro. Our data show that a decreased cross-species prion transmission does not necessarily correlate with a lack of cross-species coaggregation, suggesting that species-specificity of prion transmission is controlled at the level of conformational transition rather than coaggregation.
朊病毒是自我增殖的，并且在大多数情况下是易于聚集的蛋白质异构体，它们在哺乳动物中传播神经退行性疾病并控制酵母中的可遗传性状。朊病毒转化需要相互作用的蛋白质序列具有非常高的同一性。不同蛋白质之间朊病毒状态的传播减少被称为“种间屏障”，人们认为这是由于不同的朊病毒蛋白无法共同聚集而发生的。种间屏障可以在跨物种感染中被克服，例如从“疯牛”到人类。我们研究了酵母朊病毒蛋白Sup35的对应物，它们源自酿酒酵母严格意义组的三个不同物种，并且表现出的朊病毒结构域差异范围与在远缘哺乳动物物种中观察到的差异范围重叠。所有这三种蛋白质都能够在酿酒酵母中形成朊病毒，尽管由异源蛋白质形成的朊病毒通常比内源性酿酒酵母朊病毒更不稳定。异源Sup35蛋白在酿酒酵母细胞中共聚集。然而，在体内跨物种朊病毒转化减少，并且在体外聚合中至少在一些异源组合中受到交叉抑制，从而证明了朊病毒种间屏障的存在。此外，酿酒酵母蛋白与其奇异酿酒酵母和巴氏酿酒酵母对应物之间的屏障在体内和体外都是不对称的。我们的数据表明，跨物种朊病毒传播的减少不一定与缺乏跨物种共聚集相关，这表明朊病毒传播的物种特异性是在构象转变水平而不是共聚集水平上受到控制的。
