自噬相关WIPI家族蛋白识别WIR基序的结构机制研究

细胞自噬是溶酶体介导的一种物质降解过程，在细胞生长发育以及细胞内稳态平衡等过程中发挥重要作用。自噬相关WIPI家族蛋白特异性感应PI3P脂质信号，并通过识别特征WIR基序招募其他自噬调控因子，调控自噬体形成过程，但其识别WIR基序的结构机制目前不清楚。本项目选择WIPI家族蛋白WIPI3和ATG2A的WIR基序为主要研究对象，将综合运用结构生物学、生物化学以及细胞生物学，对WIPI3/ATG2A-WIR基序复合物进行结构与功能研究，重点研究该复合物的结构特征、ATG2A-WIR基序的作用机制、及其调控自噬体形成的生物学功能。本项目还将研究WIPI家族蛋白疾病相关突变，并鉴定含有WIR基序的新WIPI作用蛋白。通过本项目的研究，将会揭示WIPI家族蛋白识别WIR基序的分子机制，阐明其突变的致病机理以及找出潜在新WIPI作用蛋白，有利于进一步理解WIPI家族蛋白在细胞自噬调控中的功能机理。

Autophagy is a lysosome-mediated catabolic process for the clearance of damaged organelles or protein aggregates and is essential for controlling a variety of cellular processes, including cell growth, development and homeostasis. WIPI family proteins can specifically sense the PI3P signal and recognize the WIR-motif to act as scaffolds to recruit other autophagic regulators for the control of autophagosome biogenesis. However, the molecular mechanism underlying the WIR-motif recognition by WIPI family proteins remains largely unclear. In this proposal, we focus on the structural and functional studies of the WIPI family protein WIPI3 and the WIR-motif from ATG2A. By using structural biology, biochemistry and cell biology, we will work on the structure of the WIPI3/ATG2A-WIR complex, the interaction mode for ATG2A-WIR and the cellular function of this complex in regulating autophagosome formation. We will also investigate the disease-related mutations in WIPI family proteins and search out new potential WIPI-binding proteins that contain the WIR-motif. The outcome of this proposal will reveal the molecular mechanisms for the WIR-motif recognition by WIPI family proteins and their disease-related mutations and also uncover the new binding partners of WIPI family proteins, which would shed light on the understanding of the prominent role of WIPI family proteins in controlling autophagy.