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. Fun1...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.展开更多
Mitochondrial autophagy(mitophagy)is the selective clearance of damaged or incomplete mitochondria by autophagy,which is critical for the functional integrity of the entire mitochondrial network and cell survival.Beca...Mitochondrial autophagy(mitophagy)is the selective clearance of damaged or incomplete mitochondria by autophagy,which is critical for the functional integrity of the entire mitochondrial network and cell survival.Because dysfunction of mitophagy is closely related to many diseases,it is important to study the specific molecular mechanism and pathophysiological significance of mitophagy.FUN14 domain-containing 1(FUNDC1)is a newly identified mitochon-drial outer membrane protein that induces receptor-mediated mitophagy by its interaction with LC3 during hypoxia.The expression,phosphorylation,regulation and significance of FUNDC1 are reviewed in the context of a large number of pathophysiological conditions.Emerging evidence has demonstrated that levels and phosphorylation states of FUNDC1 are closely related to occur-rence,progression and prognosis of various diseases including heart diseases and cancers,indi-cating that FUNDC1 may serve as a promising biomarker and potential therapeutic target.展开更多
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）+1 种基金 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）.
文摘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.
基金This research was supported by the Natural Science Foun-dation of China[grant number 31871392]the Beijing Natural Science Foundation[grant number 5192014]+1 种基金China postdoctoral[grant number 2013 M541041]Weilin Zhang.Weilin Zhang is a recipient of the Innovation Foun-dation of Beijing University of Aeronautics and Astronautics(BUAA)and the Academic Innovation Award of Ministry of Education[grant number 401059].
文摘Mitochondrial autophagy(mitophagy)is the selective clearance of damaged or incomplete mitochondria by autophagy,which is critical for the functional integrity of the entire mitochondrial network and cell survival.Because dysfunction of mitophagy is closely related to many diseases,it is important to study the specific molecular mechanism and pathophysiological significance of mitophagy.FUN14 domain-containing 1(FUNDC1)is a newly identified mitochon-drial outer membrane protein that induces receptor-mediated mitophagy by its interaction with LC3 during hypoxia.The expression,phosphorylation,regulation and significance of FUNDC1 are reviewed in the context of a large number of pathophysiological conditions.Emerging evidence has demonstrated that levels and phosphorylation states of FUNDC1 are closely related to occur-rence,progression and prognosis of various diseases including heart diseases and cancers,indi-cating that FUNDC1 may serve as a promising biomarker and potential therapeutic target.
