Molecular mechanism of the interaction of Hsp90 with cochaperones and clients

Hsp90与共伴侣和客户相互作用的分子机制

• 批准号: 422001793
• 负责人: Professor Dr. Matthias Peter Mayer
• 金额: --
• 依托单位: Zentrum für Molekulare Biologie (ZMBH)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/422001793?language=en
• 关键词: Molecular; mechanism; interaction; Hsp90; cochaperones

The ATP dependent 90 kDa heat shock proteins (Hsp90s) are evolutionarily highly conserved and very abundant molecular chaperone that are essential in all eukaryotic cells. In cooperation with Hsp70 chaperones and, depending on the organism, more than 30 cochaperones, Hsp90s control stability and activity of many folded protein, called clients, including protein kinases, receptors, transcription factors, and a diverse set of other proteins. Many Hsp90 clients are components of essential signal transduction pathways and regulatory networks, and become only responsive to upstream signals when in complex with Hsp90 or properly folded by Hsp90. Not surprisingly, Hsp90 is involved in many human pathologies, including cancer, neurodegeneration, autoimmune diseases and infections with a wide range of pathogens, and is considered a prime drug target.The aim of this project is to further our understanding of the intricate Hsp90 machinery by (1) performing structure-function analysis of Hsp90-cochaperone complexes and Hsp90-cochaperone-client complexes, (2) screening for novel cochaperones and modifiers of the Hsp90 system necessary for the maturation of kinases in yeast, (3) analyzing the influence of posttranslational modification on conformational dynamics and function of human Hsp90. For our investigations we will use a wide range of biochemical and biophysical methods, including fluorescence techniques, hydrogen exchange mass spectrometry (HX-MS), and protein-protein interaction techniques, and genetics and molecular biology methods in baker’s yeast and mammalian cell culture.

ATP依赖的90 kDa热休克蛋白（Hsp 90 s）是一种在进化上高度保守、含量非常丰富的分子伴侣，在所有真核细胞中都是必需的。与Hsp 70分子伴侣和30多种共分子伴侣（取决于生物体）合作，Hsp 90控制许多折叠蛋白（称为客户）的稳定性和活性，包括蛋白激酶、受体、转录因子和各种其他蛋白质。许多Hsp 90客户端是重要的信号转导途径和调控网络的组成部分，并且只有在与Hsp 90复合或被Hsp 90正确折叠时才对上游信号有反应。Hsp 90参与了许多人类疾病，包括癌症、神经退行性疾病、自身免疫性疾病和多种病原体的感染，并被认为是主要的药物靶点。本项目的目的是通过（1）对Hsp 90-辅伴侣复合物和Hsp 90-辅伴侣-客户复合物进行结构-功能分析，（2）筛选酵母中激酶成熟所必需的新的辅助分子伴侣和Hsp 90系统修饰剂;（3）分析翻译后修饰对人Hsp 90构象动力学和功能的影响。对于我们的研究，我们将使用广泛的生物化学和生物物理方法，包括荧光技术，氢交换质谱（HX-MS），蛋白质-蛋白质相互作用技术，以及面包酵母和哺乳动物细胞培养中的遗传学和分子生物学方法。