Molecular Analysis of the TSC Complex

TSC复合体是一种肿瘤抑制因子，它将生长因子信号传递给mTORC1(雷帕霉素复合体1的机械靶点)激酶，以控制细胞生长。复合亚单位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，其特征是多个器官中的良性肿瘤导致器官衰竭。目前对TSC复杂功能的机制认识还很有限。在这个项目中，我们将结合小GTP酶调节因子的生物化学和结构生物学方面的专业知识，以及肿瘤细胞生物学中小GTP酶的信号转导和调控方面的专业知识，以全面了解TSC复合体的分子功能。我们希望在结构水平上对TSC复合体的组装和功能有一个详细的了解。此外，我们还将探索TSC复合体与磷脂酰肌醇磷酸盐(PIP)相互作用的分子基础，以及PIP脂类在不同生理环境下调节TSC活性的作用。我们还将描述致病患者变异对依赖TSC复合体的信号通路中TSC复合体结构、完整性和分子功能的影响。我们期望不仅对TSC复杂功能的机制有新的认识，而且对导致结节性硬化症表现的致病过程有新的认识。

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.