FUNDC1与LC3相互作用结构域在线粒体自噬调控中的关键作用

FUNDC1 作为线粒体自噬受体，它通过与LC3相互作用介导线粒体自噬。但这种相互作用如何启动线粒体自噬的分子细节尚不明了。本申请集中探讨该受体N端1-50氨基酸含有与LC3相互作用的LIR（LC3 -Interacting Region）结构域与LC3相互作用是否能够足以启动自噬，深入了解这种相互作用的结构和功能基础。首先构建含有FUNDC1其N端1-50氨基酸结构域可以分别定位到线粒体、内质网和溶酶体的融合蛋白，分析这些融合蛋白诱导不同细胞器自噬能力，研究其Ser13和Tyr18磷酸化状态调控线粒体自噬能力变化。利用NMR技术解析FUNDC1 LIR结构域与LC3作用的结构模式。明确FUNDC1介导线粒体自噬与BNIP3L/NIX线粒体自噬内在关联。本项目的实施将为受体介导线粒体自噬的分子机制提供新的认识，并为特异诱导线粒体自噬化合物的筛选打下基础。

FUNDC1 as a mitophagyreceptor contains classical LIR (LC3 Interaction Region) at the N terminal 1-50 amino acid. It remains unclear if this interaction is sufficient to promote mitophagy. Wewill focus on understanding the molecular and structural details of howLIR mediates mitophagy. First, we will construct the chimera proteins that will target FUNDC1 N terminal1-50 amino acid domain mitochondria and other organelles including endoplasmic reticulum or lysosomes and examine if these chimera proteins are able to induce organelle autophagy. Also, how the phosphorylation status at Ser13 and Tyr18 affects mitophagy will be analyzed. NMR analysis will be employed to reveal the structural details of the interaction between LIR with and LC3. Furthermore, we will compare the structural and functional details betweenLC3 with LIR motif in FUNDC1 and NIX, another known mitophagy receptor. The project will offer newinsightfor the receptor-mediatedmitophagy.