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

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 hypoxi...

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Autores principales: Lv, Mengqi, Wang, Chongyuan, Li, Fudong, Peng, Junhui, Wen, Bin, Gong, Qingguo, Shi, Yunyu, Tang, Yajun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Higher Education Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5233613/
https://www.ncbi.nlm.nih.gov/pubmed/27757847
http://dx.doi.org/10.1007/s13238-016-0328-8
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author Lv, Mengqi
Wang, Chongyuan
Li, Fudong
Peng, Junhui
Wen, Bin
Gong, Qingguo
Shi, Yunyu
Tang, Yajun
author_facet Lv, Mengqi
Wang, Chongyuan
Li, Fudong
Peng, Junhui
Wen, Bin
Gong, Qingguo
Shi, Yunyu
Tang, Yajun
author_sort Lv, Mengqi
collection PubMed
description 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 microtubule-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 FUNDC1 LIR peptide phosphorylated at Ser17 (pS(17)), 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 pS(17). Alternatively, phosphorylated Tyr18 (pY(18)) and Ser13 (pS(13)) 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 the specific recognition of FUNDC1 by LC3B and imply that the reversible phosphorylation modification of mitophagy receptors may be a switch for selective mitophagy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13238-016-0328-8) contains supplementary material, which is available to authorized users.
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spelling pubmed-52336132017-01-25 Structural insights into the recognition of phosphorylated FUNDC1 by LC3B in mitophagy Lv, Mengqi Wang, Chongyuan Li, Fudong Peng, Junhui Wen, Bin Gong, Qingguo Shi, Yunyu Tang, Yajun Protein Cell Research Article 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 microtubule-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 FUNDC1 LIR peptide phosphorylated at Ser17 (pS(17)), 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 pS(17). Alternatively, phosphorylated Tyr18 (pY(18)) and Ser13 (pS(13)) 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 the specific recognition of FUNDC1 by LC3B and imply that the reversible phosphorylation modification of mitophagy receptors may be a switch for selective mitophagy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13238-016-0328-8) contains supplementary material, which is available to authorized users. Higher Education Press 2016-10-18 2017-01 /pmc/articles/PMC5233613/ /pubmed/27757847 http://dx.doi.org/10.1007/s13238-016-0328-8 Text en © The Author(s) 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Research Article
Lv, Mengqi
Wang, Chongyuan
Li, Fudong
Peng, Junhui
Wen, Bin
Gong, Qingguo
Shi, Yunyu
Tang, Yajun
Structural insights into the recognition of phosphorylated FUNDC1 by LC3B in mitophagy
title Structural insights into the recognition of phosphorylated FUNDC1 by LC3B in mitophagy
title_full Structural insights into the recognition of phosphorylated FUNDC1 by LC3B in mitophagy
title_fullStr Structural insights into the recognition of phosphorylated FUNDC1 by LC3B in mitophagy
title_full_unstemmed Structural insights into the recognition of phosphorylated FUNDC1 by LC3B in mitophagy
title_short Structural insights into the recognition of phosphorylated FUNDC1 by LC3B in mitophagy
title_sort structural insights into the recognition of phosphorylated fundc1 by lc3b in mitophagy
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5233613/
https://www.ncbi.nlm.nih.gov/pubmed/27757847
http://dx.doi.org/10.1007/s13238-016-0328-8
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