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Exploring function and dynamics in the human VCP/p97-cofactor network

探索人类 VCP/p97 辅因子网络的功能和动态

基本信息

批准号：
235789622
负责人：
Professor Dr. Hemmo Meyer
金额：
--
依托单位：
Abteilung Molekularbiologie I
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2013
资助国家：
德国
起止时间：
2012-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/235789622?language=en
关键词：
Exploring function dynamics human VCP

项目摘要

P97 (also called VCP or Cdc48) is a ubiquitin-directed AAA+-type ATPase with a large number of diverse cellular activities that range from stress response pathways and protein degradation to intracellular signalling. They are critical for genomic stability and protein homeostasis with relevance for degenerative disease and aging. To fulfil these functions, p97 is believed to associate with alternative sets of cofactor proteins and form pathway-specific p97-cofactor complexes. However, in most cases, these complexes are only poorly defined, while - conversely - a large number of predicted cofactors have not been assigned to functional complexes.In the previous funding period, we have successfully used stress-induced cofactor localisation screening combined with functional validation to define a novel cofactor complex in one p97-mediated process, the endo-lysosomal damage response. Our goal is to now further develop and apply the approach systematically in a range of cellular stress response pathways to functionally assign p97 cofactors and define distinct pathway-specific p97 complexes. The approach will be complemented with functional studies based on cellular knock-out and RNAi approaches using a range of established readouts, as well as with biochemical and microscopic analyses of cofactor complex assembly. This will help create a comprehensive picture of the p97-cofactor system, allow comparison of p97-mediated cellular stress responses and to study their relationship upon perturbations.The expected results will close a major gap in the understanding of what has emerged as a diverse and far-reaching stress response system, and will hopefully also reveal possible strategies for therapeutic intervention in p97-associated and related degenerative disorders.

P97（也称为VCP或Cdc 48）是一种泛素导向的AAA+型ATP酶，具有大量不同的细胞活性，范围从应激反应途径和蛋白质降解到细胞内信号传导。它们对基因组稳定性和蛋白质稳态至关重要，与退行性疾病和衰老相关。为了实现这些功能，p97被认为与辅因子蛋白质的替代集合相关联，并形成通路特异性p97-辅因子复合物。然而，在大多数情况下，这些复合物只是定义不清，而-相反-大量的预测辅因子没有被分配到功能complex.In前一个资金期间，我们已经成功地使用应力诱导的辅因子定位筛选结合功能验证，以定义一个新的辅因子复合物在一个p97介导的过程中，内-溶酶体损伤反应。我们的目标是现在进一步发展和应用的方法系统地在一系列的细胞应激反应途径，功能分配p97辅因子和定义不同的途径特异性p97复合物。该方法将与基于细胞敲除和RNAi方法的功能研究相补充，使用一系列已建立的读数，以及辅因子复合物组装的生化和显微镜分析。这将有助于建立p97-辅因子系统的全面图景，允许比较p97介导的细胞应激反应，并研究它们在扰动时的关系。预期的结果将弥合理解已经出现的多样化和深远的应激反应系统的主要差距，并有望揭示p97相关和相关变性疾病的治疗干预的可能策略。