ER-associated protein degradation (ERAD): The machinery for recognition, retro-translocation and degradation of misfolded proteins of the ER

内质网相关蛋白降解 (ERAD)：内质网错误折叠蛋白的识别、逆向易位和降解机制

• 批准号: 165917224
• 负责人: Dr. Alexandra Stolz, since 1/2019
• 金额: --
• 依托单位: Abteilung für Biochemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/165917224?language=en
• 关键词: ER; associated; protein; degradation; ERAD

Correct folding of all proteins is essential for every cell. Misfolding does not only lead to loss of protein function but can also lead to the formation of protein aggregates. Also a mistaken attachment to functional proteins is possible by this inducing malfunction of the formerly functional protein. Misfolding of proteins is not only an accidental process which occurs continuously but is especially prominent upon application of stresses as heat, oxygen radicals or heavy metal ions. Also mutations constitute a prominent cause of protein misfolding. Therefore the cell possesses highly effective mechanisms of protein quality control. These mechanisms guarantee the recognition of misfolded proteins and their efficient elimination. Defects in protein quality control lead to cellular defects and constitute the cause of a multitude of severe diseases in man as are neurodegenerative diseases ( Alzheimer-, Parkinson-, Creutzfeldt Jakob disease), diabetes or cancer. All major cell compartments of a eukaryotic cell possess protein quality control and elimination mechanisms. It is the aim of this proposal to elucidate the components and mechanisms which recognize and eliminate the misfolded proteins of the endoplasmic reticulum, the central organelle of the secretory system. These studies will be done using the yeast Saccharomyces cerevisiae which has turned out to be an excellent model organism for elucidating the basic "housekeeping functions" of the eukaryotic cell. In the past, studies on this organism have resulted in groundbreaking results in the field and made yeast a pacemaker in the field of ER associated protein degradation.

所有蛋白质的正确折叠对每个细胞都是必不可少的。错误折叠不仅导致蛋白质功能丧失，而且还可能导致蛋白质聚集体的形成。通过这种诱导先前功能性蛋白质的功能障碍，也可能错误地附着到功能性蛋白质上。蛋白质的错误折叠不仅是连续发生的偶然过程，而且在施加热、氧自由基或重金属离子等应力时尤为突出。突变也是蛋白质错误折叠的主要原因。因此，细胞具有高度有效的蛋白质质量控制机制。这些机制保证了错误折叠的蛋白质的识别和有效消除。蛋白质质量控制的缺陷导致细胞缺陷，并构成人类多种严重疾病的原因，如神经退行性疾病（阿尔茨海默病、帕金森病、克雅氏病）、糖尿病或癌症。真核细胞的所有主要细胞区室都具有蛋白质质量控制和消除机制。这是本建议的目的是阐明识别和消除内质网，分泌系统的中央细胞器的错误折叠的蛋白质的组件和机制。这些研究将使用酵母酿酒酵母进行，该酵母已被证明是用于阐明真核细胞的基本“管家功能”的极好的模式生物。在过去，对这种生物体的研究已经在该领域取得了突破性的成果，并使酵母成为ER相关蛋白降解领域的起搏器。