Molecular Analysis of the TSC Complex

TSC 复合物的分子分析

• 批准号: 346246746
• 负责人: Professor Dr. Daniel Kümmel
• 金额: --
• 依托单位: Institut für Biochemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/346246746?language=en
• 关键词: Molecular; Analysis; TSC; Complex

The TSC complex is a tumor suppressor that relay growth factor signaling to the mTORC1 (mechanistic target of rapamycin complex 1) kinase to control cell growth. Mutations in the complex subunits TSC1 and TSC2 cause tuberous sclerosis complex (TSC), a genetic disease characterized by benign tumors in multiple organs that lead to organ failure. The mechanistic understanding of TSC complex function is still limited. In this project, we will combine expertise in biochemistry and structural biology of regulators of small GTPases, and signal transduction and regulation of small GTPases in tumor cell biology to obtain comprehensive insight into the molecular function of the TSC complex. We want to obtain a detailed understanding of TSC complex assembly and function on a structural level. In addition, we will explore the molecular basis for the interaction of the TSC complex with phosphatidylinositol phosphates (PIPs) and role of PIP lipids in regulating TSC activity in different physiological settings. We will also characterize the effects of pathogenic patient variants on TSC complex structure, integrity and molecular function in TSC complex-dependent signaling pathways. We expect to not only gain novel insight into the mechanism of TSC complex function, but also the pathogenic processes that lead to the manifestation of tuberous sclerosis.

TSC 复合物是一种肿瘤抑制因子，可将生长因子信号传导至 mTORC1（雷帕霉素复合物 1 的机械靶标）激酶以控制细胞生长。复杂亚基 TSC1 和 TSC2 的突变会导致结节性硬化症 (TSC)，这是一种遗传性疾病，其特征是多个器官出现良性肿瘤，导致器官衰竭。对 TSC 复杂功能的机制理解仍然有限。在该项目中，我们将结合小GTP酶调节剂的生物化学和结构生物学以及肿瘤细胞生物学中小GTP酶的信号转导和调节方面的专业知识，以全面了解TSC复合物的分子功能。我们希望在结构层面上详细了解 TSC 复杂的组装和功能。此外，我们将探讨 TSC 复合物与磷酸磷脂酰肌醇 (PIP) 相互作用的分子基础，以及 PIP 脂质在不同生理环境下调节 TSC 活性的作用。我们还将描述致病性患者变异对 TSC 复合体结构、完整性和 TSC 复合体依赖性信号通路中分子功能的影响。我们期望不仅能够获得对 TSC 复合体功能机制的新见解，而且还能获得导致结节性硬化症表现的致病过程。