SFB 969: Chemical and Biological Principles of Cellular Proteostasis

蛋白质稳态包括多个高度保守和相互关联的细胞过程，这些过程在空间和时间上控制单个蛋白质的活性，以确保蛋白质组的功能，其持续更新及其对环境变化的适应。在转录后水平上，蛋白质稳态可以定义为三个主要方面：蛋白质生物合成，包括翻译，折叠，运输和组装过程;通过翻译后修饰调节蛋白质功能，浓度和定位;蛋白质质量控制，以回收或去除错误折叠或聚集的蛋白质，以避免有毒产物在细胞内积累。众所周知，蛋白质稳态在衰老过程中自然下降，或者可以通过极端挑战达到其极限。许多人类疾病，包括癌症和神经退行性疾病，都是由蛋白质活性的失调引起的，这一事实突显了整个生物体细胞蛋白质稳态下降的深刻后果。为了剖析蛋白质稳态的基本原理，969合作研究中心（CRC）以高度跨学科和协同的研究方法，结合了化学和生物学的专业知识，以便：（i）了解在蛋白质稳态的细胞枢纽处起作用的单个蛋白质活性的调节，例如蛋白质折叠和组装、翻译后修饰和蛋白质降解。(ii)研究蛋白质组适应特定需求所需的过程和机制，如代谢变化，细胞分裂，病毒感染和压力。(iii)开发新的化学工具和生物物理策略，以模拟、监测或操纵蛋白质活性，从而在体外和体内实现蛋白质稳定。CRC 969的研究在19个项目中进行，围绕三个研究领域，反映了蛋白质的生命周期，从而反映了蛋白质稳定的关键途径：（A）蛋白质生物发生，（B）蛋白质修饰，（C）蛋白质聚集和降解。

Proteostasis comprises multiple highly conserved and interconnected cellular processes that control the activity of individual proteins in space and time to ensure the functionality of the proteome, its continuous renewal, and its adaptation to environmental changes. At the posttranscriptional level, three main aspects of proteostasis can be defined: Protein biogenesis including translation, folding, transport, and assembly processes; Modulation of protein function, concentration, and localization by posttranslational modification; Protein quality control to recycle or remove misfolded or aggregated proteins to avoid accumulation of toxic products inside the cell. It is known that proteostasis naturally declines during aging or can reach its limits by extreme challenges. The profound consequence of a decline of cellular proteostasis for the entire organism is highlighted by the fact that many human diseases including cancer and neurodegenerative disorders are caused by misregulation of protein activities.To dissect the principles underlying proteostasis, the Collaborative Research Center (CRC) 969 combines, in a highly interdisciplinary and synergistic research approach, the expertise of Chemistry and Biology in order to:(i) understand the regulation of individual protein activities that act at cellular hubs of proteostasis, e.g. in protein folding and assembly, posttranslational modification, and protein degradation. (ii) study processes and mechanisms required to adapt the proteome to specific demands such as metabolic changes, cell division, viral infection, and stress.(iii) develop novel chemical tools and biophysical strategies to simulate, monitor or manipulate protein activities and thereby proteostasis in vitro and in vivo. Research in the CRC 969 carried out in 19 projects centers around three research areas reflecting the life cycle of proteins and thus the key pathways of proteostasis: (A) Protein Biogenesis, (B) Protein Modification, and (C) Protein Aggregation and Degradation.