自噬受体蛋白NDP52、TAX1BP1、Optineurin、CCPG1识别ULK复合物的分子机制研究

细胞自噬是真核细胞内一种高度受调控的，利用溶酶体来清除受损细胞器、大型蛋白聚集体、入侵病原体等成分以应对内外界细胞压力和维持细胞自身动态平衡的重要分解代谢过程。自噬受体蛋白是一类在选择性自噬过程中发挥关键作用的接头蛋白，它可以特异性地识别目标底物，并通过招募和激活自噬起始ULK复合物来介导自噬体的形成和目标底物的包裹。目前，自噬受体蛋白招募ULK复合物的深层次的作用机制和相关的调控机理仍然未知。本申请课题将在上一个已结题项目的研究基础上，针对NDP52、TAX1BP1、Optineurin和CCPG1四个自噬受体蛋白，采用结构生物学、生物化学、细胞生物学等方法进一步研究它们未知的结构和功能关系，并着重研究它们通过结合FIP200来招募ULK复合物的分子机制及其相关的调控机理。同时，也将尝试研究ULK复合物的组装机制，并探讨这些自噬受体蛋白在结合FIP200后激活ULK复合物的分子机制。

Autophagy is a tightly regulated and lysosome-dependent intracellular catabolic process involving degradation of dysfunctional organelles, bulk protein aggregates and invading pathogens to adapt to multiple cellular stresses and to maintain cellular homeostasis in eukaryotic cells. Autophagy receptors are a group of adaptor proteins, which play crucial roles in selective autophagy processes. In selective autophagy, autophagy receptor can specifically recognize the targeting autophagic substrate, and subsequently promote the autophagosome formation and the substrate encapsulation by recruiting and activating the ULK complex that plays an essential role in the autophagy initiation. So far, the detailed molecular principles governing the interactions of autophagy receptors with ULK complex as well as the relevant regulations remain largely unknown. Based on the research foundation laid by the previous completed project, in this research proposal, we mainly focus on four important autophagy receptors, NDP52, TAX1BP1, Optineurin and CCPG1. By using multidisciplinary approaches including structure biology, biochemistry and cell biology methods, we want to further characterize the unknown structure and function relationship of these four autophagy receptors. Particularly, we will investigate the molecular mechanisms and the related regulatory mechanisms underpinning the recruitments of ULK complex by these autophagy receptors through binding to FIP200. Meanwhile, we also sought to characterize the molecular mechanism governing the assembly of ULK complex, and investigate the molecular mechanisms of the activation of ULK complex by these autophagy receptors after binding to FIP200.