Regulation of intracellular HTRA1 protease

细胞内 HTRA1 蛋白酶的调节

• 批准号: 314290915
• 负责人: Professor Dr. Michael Ehrmann
• 金额: --
• 依托单位: Zentrum für Medizinische Biotechnologie (ZMB)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/314290915?language=en
• 关键词: Regulation; intracellular; HTRA1; protease

The HtrA family represents a unique class of oligomeric serine proteases. Their defining features are the combination of a catalytic domain with C-terminal PDZ domains and that the switch between the inactive and active conformations is reversible. Even though human HTRA1 is implicated in several severe pathologies such as cancer, age-related macular degeneration, Alzheimer's disease, arthritis and familial ischemic cerebral small-vessel disease, close to nothing is known about how this protease is regulated in the cell. The main objective of this proposal is therefore to identify and analyse cellular factors involved in regulating the activity of cytoplasmic HTRA1 and to characterise the corresponding physiologic consequences. To identify the underlying molecular mechanisms, protein complexes between HTRA1 and its regulatory ligands as well as posttranslational modifications will be studied. These data will allow us to address the important question in which cellular processes the regulation of HTRA1 is of particular importance. Correspondingly, these studies are expected to reveal deeper insights into the roles of this widely conserved protease in protein homeostasis of human cells.

HtrA家族代表一类独特的寡聚丝氨酸蛋白酶。它们的定义特征是催化结构域与C-末端PDZ结构域的组合，并且非活性和活性构象之间的转换是可逆的。尽管人类HTRA 1与几种严重的病理学有关，如癌症、年龄相关性黄斑变性、阿尔茨海默病、关节炎和家族性缺血性脑小血管病，但对这种蛋白酶在细胞中如何调节几乎一无所知。因此，本提案的主要目的是鉴定和分析参与调节细胞质HTRA 1活性的细胞因子，并阐明相应的生理后果。为了确定潜在的分子机制，将研究HTRA 1及其调节配体之间的蛋白质复合物以及翻译后修饰。这些数据将使我们能够解决一个重要的问题，即在细胞过程中，HTRA 1的调节特别重要。相应地，这些研究有望揭示这种广泛保守的蛋白酶在人类细胞蛋白质稳态中的作用。