Regulation by Proteolysis-Independent Ubiquitination

泛素化，即小蛋白泛素与其他蛋白质的共价结合，调节了一系列 细胞过程。蛋白质泛素化已成为蛋白质降解的代名词。然而，我们正在 开始意识到一些蛋白质是由泛素化调节的，不依赖于蛋白水解酶 举止。目前的研究大多集中在泛素在靶向蛋白质中的作用。 26S蛋白酶体的降解。然而，蛋白质组的方法表明，许多蛋白质是 受蛋白质降解非依赖泛素化的调控，对这些过程的详细了解是 显然对生物医学研究很重要。其中一些关键问题是：为什么有些人是泛素化的 蛋白质会被降解，而其他蛋白质不会？泛素化是如何直接影响蛋白质活性的？会不会有蛋白质 是由泛素共享序列结构域以不依赖于蛋白降解的方式调节的？在本建议书中 我们以酵母转录因子Met4为模型，研究蛋白质活性的调控机制 通过非蛋白水解型泛素化；泛素结合域在保护 26S蛋白酶体降解泛素化蛋白及其泛素结合域的作用 调节泛素链长(目标2)；以及通过以下方式调节蛋白质活性的生理益处 泛素化而不降解(目标3)。在目标4中，我们使用蛋白质组范围的方法来鉴定蛋白质 受蛋白质降解非依赖泛素化调控，并应用生物信息学策略识别 共享的蛋白质结构域。 泛素化影响许多重要的细胞过程，并与许多人类 包括癌症、神经变性和逆转录病毒感染在内的疾病。非蛋白水解性的贡献 这些疾病中的泛素化正在出现，了解 这一规定背后的机制，以设计诊断工具和治疗策略。这项建议旨在 深入了解泛素对蛋白质降解的独立调控机制，并定义一些 这一调节泛素化途径的特征。

Ubiquitination, the covalent attachment of the small protein ubiquitin to other proteins, regulates a host of cellular processes. Protein Ubiquitination has become a synonym for protein degradation. However, we are beginning to appreciate that a number of proteins are regulated by Ubiquitination in a proteolysisindependent manner. Most of the current research is focused on the role of ubiquitin in targeting proteins for degradation by the 26S proteasome. However, proteome-wide approaches indicate that many proteins are regulated by proteolysis-independent Ubiquitination and a detailed understanding of these processes is clearly important for biomedical research. Some of the key questions are: Why are some ubiquitinated proteins degraded and others are not? How can Ubiquitination directly affect protein activity? Do proteins that are regulated in a proteolysis-independent manner by ubiquitin share sequence domains? In this proposal we use the yeast transcription factor Met4 as a model to study the mechanism of regulation of protein activity by proteolysis-independent Ubiquitination (aiml); the role of ubiquitin-binding domains in protecting ubiquitinated proteins from degradation by the 26S proteasome and the role of ubiquitin-binding domains in regulating ubiquitin chain length (aim 2); and the physiological benefit of regulating protein activity by Ubiquitination without degradation (aim 3). In aim 4 we use a proteome-wide approach to identify proteins that are regulated by proteolysis-independent Ubiquitination and apply a bioinformatics strategy to identify shared protein domains. Ubiquitination affects many important cellular processes and has been linked to a number of human diseases including cancer, neurodegeneration, and retroviral infection. A contribution of proteolysisindependent Ubiquitination in these diseases is emerging and it will be important to understand the mechanism behind this regulation to design diagnostic tools and treatment strategies. This proposal aims to achieve detailed mechanistic insight into proteolysis-independent regulation by ubiquitin and to define some of the characteristics of this regulatory Ubiquitination pathway.