YEAST PRION FACTOR (PSI+)

某些神经退行性疾病，如羊瘙痒症，疯牛病 和人类的克雅氏病，似乎是由一种 感染性蛋白质，称为朊病毒，没有任何核酸。 朊病毒， 被认为是一种细胞蛋白质的改变形式， 正常蛋白质（PrPC）转变成朊病毒（PrPSc）构象。 最近 有证据表明朊病毒并不局限于 哺乳动物的情况下，但这两种酵母蛋白质也可以采取自我- 传播“朊病毒”构象 因此，遗传变异性 仅在蛋白质构象水平上可能是广泛使用的机制 继承权 酵母菌是一种理想的生物体， 朊病毒遗传的基础知识 因此，详细的基因和 酵母[PSI+]因子的生物化学研究，这是一种朊病毒形式， Sup 35 p =真核细胞释放因子eRF 3）。 存在不同的羊瘙痒病菌株，这表明 病毒核酸的突变对朊病毒假说提出了挑战。 酵母[PSI+]朊病毒的类似变体， 由病毒引起的，最近已经获得了这项研究，支持 不同的朊病毒株对应于不同的自身免疫的观点， 繁殖朊病毒蛋白构象。 [ETA+]因素，此前 PI发现的，将进行调查，以确定它是否是 新的朊病毒或[PSI+]朊病毒的变体。 有证据表明 Sup 35 p的不同功能（即[psi-]）构象的存在， 其中一些也是自我繁殖的朊病毒，将被探索。 的 所有[PSI+]和[PSI-]变体的生化特性和规则 控制它们的遗传和遗传相互作用的基因将被定义。 对哺乳动物朊病毒株进行类似的遗传分析， 难 [PSI]朊病毒蛋白Sup 35 p的结构/功能分析将 也要承担。 Sup 35 p的小肽可以和不能诱导 [PSI+]，以标记涉及[PSI+]的Sup 35 p区域。 入职培训和维护。 将获得SUP 35中的突变， 刺激[PSI+]的自发出现，因此类似 哺乳动物朊病毒基因的“家族性”突变。 哺乳动物 家族性突变似乎增加了正常折叠的倾向， PrPC蛋白翻转成朊病毒构象，从而导致 朊病毒病 防止Sup 35蛋白质从基因组中表达的 在没有[PSI +]的情况下成为[PSI+]“种子”也将是 获得并表征。 最后，影响[PSI+]诱导或繁殖的新基因 朊病毒将被鉴定，并且已知几个基因与SUP 35相互作用 将专门测试其对[PSI+]的影响。

Certain neurodegenerative diseases, such as sheep scrapie, mad cow disease and Creutzfeldt-Jacob disease in humans, appear to be transmitted by an infectious protein, called a prion, without any nucleic acid. The prion, is proposed to be an altered form of a cellular protein which can convert the normal protein (PrPC) into its prion PrPSc) conformation. Recent evidence indicates what prions are not limited to the well characterized mammalian case, but that two yeast proteins can also take on self- propagating "prion" conformations. Thus, genetic variability operating solely at the level of protein conformation may be a widely used mechanism of inheritance. Yeast is an ideal organism in which to investigate the basics of the prion form of inheritance. Thus, detailed genetic and biochemical studies of the yeast [PSI+] factor, which is a prion form of the Sup35p=eukaryotic release factor eRF3), are proposed. The existence of different scrapie strains, which are suggestive of mutations in viral nucleic acid, has challenged the prion hypothesis. Analogous variants of the yeast [PSI+] prion, that could not have been caused by viruses, have recently been obtained for this study, supporting the view that different prion strains correspond to distinct self- propagating prion protein conformations. The [ETA+] factor, previously discovered by the PI, will be investigated to determine whether it is a new prion or a variant of the [PSI+] prion. Suggestive evidence for the existence of different functional (i.e. [psi-]) conformations of Sup35p, some of which are also self-propagating prions, will be explored. The biochemical properties of all [PSI+] and [psi-] variants and the rules that govern their inheritance and genetic interactions will be defined. Similar genetic analyses of mammalian prion strains would be much more difficult. A structure/function analysis of the [PSI] prion protein, Sup35p, will also be undertaken. Small peptides of Sup35p that can and cannot induce [PSI+], will be obtained to mark regions of Sup35p involved in [PSI+] induction and maintenance. Mutations in SUP35 will be obtained that stimulate the spontaneous appearance of [PSI+] and are therefore analogous to "familial" mutations in the mammalian prion gene. The mammalian familial mutations appear to increase the inclination of normally folded PrPC protein to flip into the prion conformation, thereby causing the prion disease. New alleles of SUP35 that prevent the Sup35 protein from becoming [PSI+] in the presence of absence of [PSI+] "seeds" will also be obtained and characterized. Finally, new genes that affect the induction or propagation of the [PSI+] prion will be identified and several genes known to interact with SUP35 will be specifically tested for their effects on [PSI+].