Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati, Via Bonomea 265, I-34136 Trieste, Italy; Italian Institute of Technology, Scuola Internazionale Superiore di Studi Avanzati Unit, Via Bonomea 265, I-34136 Trieste, Italy.
Department of Physics, Scuola Internazionale Superiore di Studi Avanzati, I-34136 Trieste, Italy.
J Mol Biol. 2014 Nov 11;426(22):3796-3810. doi: 10.1016/j.jmb.2014.09.017. Epub 2014 Oct 2.
Prions are responsible for a heterogeneous group of fatal neurodegenerative diseases, involving post-translational modifications of the cellular prion protein. Epidemiological studies on Creutzfeldt-Jakob disease, a prototype prion disorder, show a majority of cases being sporadic, while the remaining occurrences are either genetic or iatrogenic. The molecular mechanisms by which PrP(C) is converted into its pathological isoform have not yet been established. While point mutations and seeds trigger the protein to cross the energy barriers, thus causing genetic and infectious transmissible spongiform encephalopathies, respectively, the mechanism responsible for sporadic forms remains unclear. Since prion diseases are protein-misfolding disorders, we investigated prion protein folding and stability as functions of different milieus. Using spectroscopic techniques and atomistic simulations, we dissected the contribution of major structural determinants, also defining the energy landscape of prion protein. In particular, we elucidated (i) the essential role of the octapeptide region in prion protein folding and stability, (ii) the presence of a very enthalpically stable intermediate in prion-susceptible species, and (iii) the role of the disulfide bridge in prion protein folding.
朊病毒负责一组异质的致命神经退行性疾病，涉及细胞朊病毒蛋白的翻译后修饰。对克雅氏病（一种朊病毒疾病原型）的流行病学研究表明，大多数病例为散发性，而其余病例则为遗传性或医源性。PrP(C) 转化为其病理性异构体的分子机制尚未确定。虽然点突变和种子触发蛋白质跨越能量障碍，从而分别导致遗传性和传染性海绵状脑病，但散发性形式的机制仍不清楚。由于朊病毒疾病是蛋白质错误折叠疾病，我们研究了不同环境下朊病毒蛋白折叠和稳定性作为功能。使用光谱技术和原子模拟，我们剖析了主要结构决定因素的贡献，还定义了朊病毒蛋白的能量景观。特别是，我们阐明了（i）八肽区域在朊病毒蛋白折叠和稳定性中的重要作用，（ii）在朊病毒易感物种中存在非常焓稳定的中间产物，以及（iii）二硫键在朊病毒蛋白折叠中的作用。
