Tank Elizabeth M H, Harris David A, Desai Amar A, True Heather L
Department of Cell Biology and Physiology, Washington University School of Medicine, Campus Box 8228, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
Mol Cell Biol. 2007 Aug;27(15):5445-55. doi: 10.1128/MCB.02127-06. Epub 2007 Jun 4.
Mammalian prion diseases are fatal neurodegenerative disorders dependent on the prion protein PrP. Expansion of the oligopeptide repeats (ORE) found in PrP is associated with inherited prion diseases. Patients with ORE frequently harbor PrP aggregates, but other factors may contribute to pathology, as they often present with unexplained phenotypic variability. We created chimeric yeast-mammalian prion proteins to examine the influence of the PrP ORE on prion properties in yeast. Remarkably, all chimeric proteins maintained prion characteristics. The largest repeat expansion chimera displayed a higher propensity to maintain a self-propagating aggregated state. Strikingly, the repeat expansion conferred increased conformational flexibility, as observed by enhanced phenotypic variation. Furthermore, the repeat expansion chimera displayed an increased rate of prion conversion, but only in the presence of another aggregate, the [RNQ+] prion. We suggest that the PrP ORE increases the conformational flexibility of the prion protein, thereby enhancing the formation of multiple distinct aggregate structures and allowing more frequent prion conversion. Both of these characteristics may contribute to the phenotypic variability associated with PrP repeat expansion diseases.
哺乳动物朊病毒疾病是依赖于朊病毒蛋白PrP的致命性神经退行性疾病。在PrP中发现的寡肽重复序列（ORE）的扩展与遗传性朊病毒疾病有关。ORE患者经常携带PrP聚集体，但其他因素可能也会导致病变，因为他们常常表现出无法解释的表型变异性。我们构建了嵌合酵母 - 哺乳动物朊病毒蛋白，以研究PrP ORE对酵母中朊病毒特性的影响。值得注意的是，所有嵌合蛋白都保持了朊病毒特征。最大的重复序列扩展嵌合体表现出更高的维持自我传播聚集状态的倾向。令人惊讶的是，如通过增强的表型变异所观察到的，重复序列扩展赋予了更高的构象灵活性。此外，重复序列扩展嵌合体显示出更高的朊病毒转化速率，但仅在存在另一种聚集体即[RNQ+]朊病毒的情况下。我们认为，PrP ORE增加了朊病毒蛋白的构象灵活性，从而增强了多种不同聚集结构的形成，并允许更频繁的朊病毒转化。这两个特征都可能导致与PrP重复序列扩展疾病相关的表型变异性。
