Structural insights of phosphorylated into the recognition FUNDC1 by LC3B in mitophagy

作     者：Mengqi Lv Chongyuan Wang Fudong Li Junhui Peng Bin Wen Qingguo Gong Yunyu Shi Yajun-Tang 

作者机构：Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences University of Science and Technology of China Hefei 230027 China 

出 版 物：《Protein & Cell》 (蛋白质与细胞（英文版）)

年 卷 期：2017年第8卷第1期

页      面：25-38页

核心收录：

学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 081704[工学-应用化学] 07[理学] 08[工学] 0817[工学-化学工程与技术] 09[农学] 0904[农学-植物保护] 090401[农学-植物病理学] 

基　　金：This work was supported by National Natural Science Founda- tion (Grant No. 31400629) the Strategic Priority Research Program of the Chinese Academy of Science (No. XDB08010101) Ministry Of Science And Technology of China (No. 2016YFA0500700) China Postdoctoral Science Foundation (No. 2015M582009 and 2016T90579) and National Natural Science Foundation (Grant No. 31330018) 

主　　题：microtubule-associated protein light chain 3 beta (LC3B) fun14 domain-containing protein 1 (FUNDC1) phosphorylation selective mitophagy 

摘      要：Mitophagy is an essential intracellular process that eliminates dysfunctional mitochondria and maintains cellular homeostasis. Mitophagy is regulated by the post-translational modification of mitophagy receptors. Fun14 domain-containing protein 1 （FUNDC1） was reported to be a new receptor for hypoxia-induced mitophagy in mammalian cells and interact with micro-tubule-associated protein light chain 3 beta （LC3B） through its LC3 interaction region （LIR）. Moreover, the phosphorylation modification of FUNDC1 affects its binding affinity for LC3B and regulates selective mitophagy. However, the structural basis of this regulation mechanism remains unclear. Here, we present the crystal structure of LC3B in complex with a FUNDCI LIR peptide phosphorylated at Ser17 （pS17）, demonstrating the key residues of LC3B for the specific recognition of the phosphorylated or dephosphorylated FUNDC1. Intriguingly, the side chain of LC3B Lys49 shifts remarkably and forms a hydrogen bond and electrostatic interaction with the phosphate group of FUNDC1 pS17. Alternatively, phosphorylated Tyr18 （PY18） and Ser13 （PS13） in FUNDC1 significantly obstruct their interaction with the hydrophobic pocket and Arg10 of LC3B, respectively. Structural observations are further validated by mutation and isothermal titration calorimetry （ITC） assays. Therefore, our structural and biochemical results reveal a working model for thespecific recognition of FUNDCI by LC3B and imply that the reversible phosphorylation modification of mitophagy receptors may be a switch for selective mitophagy.