Distinct type of transmission barrier revealed by study of multiple prion determinants of Rnq1.
Distinct type of transmission barrier revealed by study of multiple prion determinants of Rnq1.
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DOI：
10.1371/journal.pgen.1000824
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发表时间：
2010-01-22
期刊：
影响因子：
4.5
通讯作者：
Derkatch IL
中科院分区：
文献类型：
--
作者：
Kadnar ML;Articov G;Derkatch IL
朊病毒是自我繁殖的蛋白质构象。朊病毒状态在不同蛋白质之间的传递，例如来自不同物种的同源蛋白质之间的传递，通常是低效的。传递障碍归因于朊病毒蛋白的序列差异，但其潜在机制尚不清楚。在这里，我们使用酵母Rnq 1/[PIN+]为基础的实验系统，探索传输障碍的性质。[PIN+]，Rnq 1的朊病毒形式，在野生和实验室酵母菌株中很常见，它促进了其他朊病毒的出现。Rnq 1的朊病毒结构域携带四个离散的QN富集区。我们首先表明，Rnq 1包含多个朊病毒的决定因素，可以独立地驱动淀粉样蛋白的形成在体外和传输的[PIN+]朊病毒状态在体内。随后对具有不同朊病毒决定簇的Rnq 1片段之间的[PIN+]传输进行了分析，结果表明：（i）需要一个共同的富含QN的区域，并且通常足以进行传输;（ii）尽管共同QN的序列相同，但这种传输受到不同强度的屏障的阻碍。在传输区域的氨基酸不匹配的情况下，传输障碍的存在表明，在复杂的朊病毒结构域的多个朊病毒决定因素合作，以达到最终的朊病毒构象，并揭示了传输障碍，由这种合作的折叠。朊病毒是一种自我繁殖的蛋白质构象，是致命的神经变性疾病的病原体，对公共卫生构成严重威胁：它们可以零星出现，然后通过传播传播给同一物种以及其他物种。源自野生动物和家畜的朊病毒感染人类的风险取决于所谓的传播障碍。这些障碍归因于不同物种朊病毒蛋白的差异，但其潜在机制尚不清楚。最近的研究发现，朊病毒状态是通过朊病毒结构域内的短传输区域之间的相互作用传递的，揭示了一种类型的传输障碍，其中生产性模板被传输区域内的非匹配氨基酸所阻碍。在这里，我们目前的研究朊病毒结构域的[PIN+]形成蛋白质，Rnq 1，并描述了一种不同类型的传输屏障不涉及个别氨基酸的不匹配的传输区域。rnq 1的朊病毒结构域很复杂，包含四个可以独立传递朊病毒状态的区域。我们的数据表明，一个复杂的朊病毒结构域的多个朊病毒决定因素合作，以达到朊病毒的构象，和传输障碍之间发生的蛋白质变体，不能形成相同的高阶结构，尽管该地区的身份（S）驱动传输。
Prions are self-propagating protein conformations. Transmission of the prion state between non-identical proteins, e.g. between homologous proteins from different species, is frequently inefficient. Transmission barriers are attributed to sequence differences in prion proteins, but their underlying mechanisms are not clear. Here we use a yeast Rnq1/[PIN+]-based experimental system to explore the nature of transmission barriers. [PIN+], the prion form of Rnq1, is common in wild and laboratory yeast strains, where it facilitates the appearance of other prions. Rnq1's prion domain carries four discrete QN-rich regions. We start by showing that Rnq1 encompasses multiple prion determinants that can independently drive amyloid formation in vitro and transmit the [PIN+] prion state in vivo. Subsequent analysis of [PIN+] transmission between Rnq1 fragments with different sets of prion determinants established that (i) one common QN-rich region is required and usually sufficient for the transmission; (ii) despite identical sequences of the common QNs, such transmissions are impeded by barriers of different strength. Existence of transmission barriers in the absence of amino acid mismatches in transmitting regions indicates that in complex prion domains multiple prion determinants act cooperatively to attain the final prion conformation, and reveals transmission barriers determined by this cooperative fold. Prions, self-propagating protein conformations and causative agents of lethal neurodegenerative diseases, present a serious public health threat: they can arise sporadically and then spread by transmission to the same, as well as other, species. The risk of infecting humans with prions originating in wild and domestic animals is determined by the so-called transmission barriers. These barriers are attributed to differences in prion proteins from different species, but their underlying mechanisms are not clear. Recent findings that the prion state is transmitted through the interaction between short transmitting regions within prion domains revealed one type of transmission barrier, where productive templating is impeded by non-matching amino acids within transmitting regions. Here we present studies of the prion domain of the [PIN+]-forming protein, Rnq1, and describe a distinct type of transmission barrier not involving individual amino acid mismatches in the transmitting regions. Rnq1's prion domain is complex and encompasses four regions that can independently transmit the prion state. Our data suggest that multiple prion determinants of a complex prion domain act cooperatively to attain the prion conformation, and transmission barriers occur between protein variants that cannot form the same higher order structure, despite the identity of the region(s) driving the transmission.
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