PROTEIN PROTEIN INTERACTIONS DURING PRION PROTEIN BIOGENESIS

朊病毒蛋白生物发生过程中的蛋白质相互作用

• 批准号: 6097929
• 负责人: VISHWANATH R LINGAPPA
• 金额: $ 22.21万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6097929
• 关键词: cell free system; cell line; crosslink; disease /disorder model; endoplasmic reticulum; genetically modified animals; immunoprecipitation; intracellular transport; laboratory mouse; molecular pathology; mutant; neural degeneration; phenotype; prions; protein biosynthesis; protein engineering; protein localization; protein protein interaction; protein sequence; protein transport; scrapie; transfection

At the endoplasmic reticulum (ER) membrane, nascent prion protein (PrP) can be synthesized in both fully translocated and transmembrane forms, as a result of the action of Translocation Accessory Factors (TrAFs). The relevance of these observations has recently become apparent with the demonstration of spontaneous neurodegenerative disease in both mice and humans expressing PrP mutations that favor synthesis and export of transmembrane PrP from the ER. Some evidence suggests that the expression of neurodegeneration -associated transmembrane PrP may be a default outcome in the absence of TrAF activity. The investigation of topological regulation during PrP biogenesis is crucial for an understanding the molecular pathogenesis of these genetic prion diseases. Here we propose to dissect the mechanisms by which PrP biogenesis affects PrP topology disease. Here we propose to dissect the mechanism by which PrP biogenesis affects PrP topology, resulting in an transmembrane form that leads to neurodegeneration. Mutations in PrP structural domains will be systematically correlated to effects on topological regulation. Trafficking of selected mutants will be studied in transfected cells. Transgenic mouse model systems will be developed for those mutants with the most interesting phenotypes. Protein-protein interactions between the translocation machinery and nascent PrP will be identified and correlated with the pathway of neurodegeneration. Through this work, the pathway of PrP biogenesis, as it relates to a newly recognized pathway of neurodegeneration, will be better understood in molecular terms. In the long run these studies should make possible novel approaches to manipulation of PrP topology and may contribute to prevention or treatment of prion diseases and other neurodegenerative disease.

在内质网 (ER) 膜上，由于易位辅助因子 (TrAF) 的作用，新生朊病毒蛋白 (PrP) 可以完全易位和跨膜形式合成。最近，随着表达 PrP 突变的小鼠和人类中自发性神经退行性疾病的证明，这些观察结果的相关性变得明显，这些突变有利于跨膜 PrP 从 ER 的合成和输出。一些证据表明，在缺乏 TrAF 活性的情况下，神经退行性变相关的跨膜 PrP 的表达可能是默认结果。 PrP 生物发生过程中拓扑调控的研究对于理解这些遗传性朊病毒疾病的分子发病机制至关重要。在这里，我们建议剖析 PrP 生物发生影响 PrP 拓扑疾病的机制。在这里，我们建议剖析 PrP 生物发生影响 PrP 拓扑结构的机制，从而产生导致神经变性的跨膜形式。 PrP 结构域的突变将与拓扑调节的影响系统相关。将在转染细胞中研究选定突变体的贩运。将为那些具有最有趣表型的突变体开发转基因小鼠模型系统。易位机制和新生 PrP 之间的蛋白质-蛋白质相互作用将被识别，并与神经变性的途径相关联。通过这项工作，PrP 生物发生途径，因为它与新认识的神经变性途径相关，将在分子术语上得到更好的理解。从长远来看，这些研究应该使操纵 PrP 拓扑的新方法成为可能，并可能有助于预防或治疗朊病毒疾病和其他神经退行性疾病。