3wal Citations

Structural basis of the autophagy-related LC3/Atg13 LIR complex: recognition and interaction mechanism.

Structure 22 47-58 (2014)
Related entries: 3wam, 3wan, 3wao, 3wap

Cited: 72 times
EuropePMC logo PMID: 24290141

Abstract

Autophagy is a bulk degradation pathway that removes cytosolic materials to maintain cellular homeostasis. The autophagy-related gene 13 (Atg13) and microtubule associate protein 1 light chain 3 (LC3) proteins are required for autophagosome formation. We demonstrate that each of the human LC3 isoforms (LC3A, LC3B, and LC3C) interacts with Atg13 via the LC3 interacting region (LIR) of Atg13. Using X-ray crystallography, we solved the macromolecular structures of LC3A and LC3C, along with the complex structures of the LC3 isoforms with the Atg13 LIR. Together, our structural and binding analyses reveal that the side-chain of Lys49 of LC3 acts as a gatekeeper to regulate binding of the LIR. We verified this observation by mutation of Lys49 in LC3A, which significantly reduces LC3A positive puncta formation in cultured cells. Our results suggest that specific affinity of the LC3 isoforms to the Atg13 LIR is required for proper autophagosome formation.

Reviews - 3wal mentioned but not cited (2)

  1. Post-translationally-modified structures in the autophagy machinery: an integrative perspective. Popelka H, Klionsky DJ. FEBS J 282 3474-3488 (2015)
  2. Emerging degrader technologies engaging lysosomal pathways. Ding Y, Xing D, Fei Y, Lu B. Chem Soc Rev 51 8832-8876 (2022)

Articles - 3wal mentioned but not cited (7)

  1. Structural basis of FYCO1 and MAP1LC3A interaction reveals a novel binding mode for Atg8-family proteins. Cheng X, Wang Y, Gong Y, Li F, Guo Y, Hu S, Liu J, Pan L. Autophagy 12 1330-1339 (2016)
  2. Human LC3 and GABARAP subfamily members achieve functional specificity via specific structural modulations. Jatana N, Ascher DB, Pires DEV, Gokhale RS, Thukral L. Autophagy 16 239-255 (2020)
  3. Autophagy gene expression profiling identifies a defective microtubule-associated protein light chain 3A mutant in cancer. Costa JR, Prak K, Aldous S, Gewinner CA, Ketteler R. Oncotarget 7 41203-41216 (2016)
  4. Human ubiquitin-like proteins as central coordinators in autophagy. Mohan J, Wollert T. Interface Focus 8 20180025 (2018)
  5. Interaction of TBC1D9B with Mammalian ATG8 Homologues Regulates Autophagic Flux. Liao Y, Li M, Chen X, Jiang Y, Yin XM. Sci Rep 8 13496 (2018)
  6. An ALS-associated variant of the autophagy receptor SQSTM1/p62 reprograms binding selectivity toward the autophagy-related hATG8 proteins. Brennan A, Layfield R, Long J, Williams HEL, Oldham NJ, Scott D, Searle MS. J Biol Chem 298 101514 (2022)
  7. Crystallographic Characterization of ATG Proteins and Their Interacting Partners. Qiu Y, Zheng Y, Taherbhoy AM, Kaiser SE, Schulman BA. Methods Enzymol 587 227-246 (2017)


Reviews citing this publication (16)

  1. Ubiquitin-like Protein Conjugation: Structures, Chemistry, and Mechanism. Cappadocia L, Lima CD. Chem Rev 118 889-918 (2018)
  2. Mechanisms of Autophagy. Noda NN, Inagaki F. Annu Rev Biophys 44 101-122 (2015)
  3. Dynamic regulation of macroautophagy by distinctive ubiquitin-like proteins. Klionsky DJ, Schulman BA. Nat Struct Mol Biol 21 336-345 (2014)
  4. Structure and function of the ULK1 complex in autophagy. Lin MG, Hurley JH. Curr Opin Cell Biol 39 61-68 (2016)
  5. Atomistic autophagy: the structures of cellular self-digestion. Hurley JH, Schulman BA. Cell 157 300-311 (2014)
  6. Atg1 family kinases in autophagy initiation. Noda NN, Fujioka Y. Cell Mol Life Sci 72 3083-3096 (2015)
  7. Mitochondria-associated ER membranes (MAMs) and lysosomal storage diseases. Annunziata I, Sano R, d'Azzo A. Cell Death Dis 9 328 (2018)
  8. So Many Roads: the Multifaceted Regulation of Autophagy Induction. Corona Velazquez AF, Jackson WT. Mol Cell Biol 38 e00303-18 (2018)
  9. History of the Selective Autophagy Research: How Did It Begin and Where Does It Stand Today? Kirkin V. J Mol Biol 432 3-27 (2020)
  10. ATG13: just a companion, or an executor of the autophagic program? Alers S, Wesselborg S, Stork B. Autophagy 10 944-956 (2014)
  11. Beyond starvation: An update on the autophagic machinery and its functions. Kawabata T, Yoshimori T. J Mol Cell Cardiol 95 2-10 (2016)
  12. Anatomy of autophagy: from the beginning to the end. Zhi X, Feng W, Rong Y, Liu R. Cell Mol Life Sci 75 815-831 (2018)
  13. Atg8-Family Proteins-Structural Features and Molecular Interactions in Autophagy and Beyond. Wesch N, Kirkin V, Rogov VV. Cells 9 E2008 (2020)
  14. Mitochondrial Mutations and Genetic Factors Determining NAFLD Risk. Dabravolski SA, Bezsonov EE, Baig MS, Popkova TV, Nedosugova LV, Starodubova AV, Orekhov AN. Int J Mol Sci 22 4459 (2021)
  15. Structure and Dynamics in the ATG8 Family From Experimental to Computational Techniques. Sora V, Kumar M, Maiani E, Lambrughi M, Tiberti M, Papaleo E. Front Cell Dev Biol 8 420 (2020)
  16. The Interplay of HIV and Autophagy in Early Infection. Cabrera-Rodríguez R, Pérez-Yanes S, Estévez-Herrera J, Márquez-Arce D, Cabrera C, Espert L, Blanco J, Valenzuela-Fernández A. Front Microbiol 12 661446 (2021)

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  1. Translocon component Sec62 acts in endoplasmic reticulum turnover during stress recovery. Fumagalli F, Noack J, Bergmann TJ, Cebollero E, Pisoni GB, Fasana E, Fregno I, Galli C, Loi M, Soldà T, D'Antuono R, Raimondi A, Jung M, Melnyk A, Schorr S, Schreiber A, Simonelli L, Varani L, Wilson-Zbinden C, Zerbe O, Hofmann K, Peter M, Quadroni M, Zimmermann R, Molinari M. Nat Cell Biol 18 1173-1184 (2016)
  2. Phosphorylation of the mitochondrial autophagy receptor Nix enhances its interaction with LC3 proteins. Rogov VV, Suzuki H, Marinković M, Lang V, Kato R, Kawasaki M, Buljubašić M, Šprung M, Rogova N, Wakatsuki S, Hamacher-Brady A, Dötsch V, Dikic I, Brady NR, Novak I. Sci Rep 7 1131 (2017)
  3. Structural and functional analysis of the GABARAP interaction motif (GIM). Rogov VV, Stolz A, Ravichandran AC, Rios-Szwed DO, Suzuki H, Kniss A, Löhr F, Wakatsuki S, Dötsch V, Dikic I, Dobson RC, McEwan DG. EMBO Rep 18 1382-1396 (2017)
  4. FYCO1 Contains a C-terminally Extended, LC3A/B-preferring LC3-interacting Region (LIR) Motif Required for Efficient Maturation of Autophagosomes during Basal Autophagy. Olsvik HL, Lamark T, Takagi K, Larsen KB, Evjen G, Øvervatn A, Mizushima T, Johansen T. J Biol Chem 290 29361-29374 (2015)
  5. Cargo binding to Atg19 unmasks additional Atg8 binding sites to mediate membrane-cargo apposition during selective autophagy. Sawa-Makarska J, Abert C, Romanov J, Zens B, Ibiricu I, Martens S. Nat Cell Biol 16 425-433 (2014)
  6. Structural insights into the recognition of phosphorylated FUNDC1 by LC3B in mitophagy. Lv M, Wang C, Li F, Peng J, Wen B, Gong Q, Shi Y, Tang Y. Protein Cell 8 25-38 (2017)
  7. Structural basis for the phosphorylation of FUNDC1 LIR as a molecular switch of mitophagy. Kuang Y, Ma K, Zhou C, Ding P, Zhu Y, Chen Q, Xia B. Autophagy 12 2363-2373 (2016)
  8. Molecular determinants regulating selective binding of autophagy adapters and receptors to ATG8 proteins. Wirth M, Zhang W, Razi M, Nyoni L, Joshi D, O'Reilly N, Johansen T, Tooze SA, Mouilleron S. Nat Commun 10 2055 (2019)
  9. Structural Basis of the Differential Function of the Two C. elegans Atg8 Homologs, LGG-1 and LGG-2, in Autophagy. Wu F, Watanabe Y, Guo XY, Qi X, Wang P, Zhao HY, Wang Z, Fujioka Y, Zhang H, Ren JQ, Fang TC, Shen YX, Feng W, Hu JJ, Noda NN, Zhang H. Mol Cell 60 914-929 (2015)
  10. Structure of the Human Atg13-Atg101 HORMA Heterodimer: an Interaction Hub within the ULK1 Complex. Qi S, Kim DJ, Stjepanovic G, Hurley JH. Structure 23 1848-1857 (2015)
  11. TBK1-mediated phosphorylation of LC3C and GABARAP-L2 controls autophagosome shedding by ATG4 protease. Herhaus L, Bhaskara RM, Lystad AH, Gestal-Mato U, Covarrubias-Pinto A, Bonn F, Simonsen A, Hummer G, Dikic I. EMBO Rep 21 e48317 (2020)
  12. A novel selective autophagy receptor, CCDC50, delivers K63 polyubiquitination-activated RIG-I/MDA5 for degradation during viral infection. Hou P, Yang K, Jia P, Liu L, Lin Y, Li Z, Li J, Chen S, Guo S, Pan J, Wu J, Peng H, Zeng W, Li C, Liu Y, Guo D. Cell Res 31 62-79 (2021)
  13. PEBP1, a RAF kinase inhibitory protein, negatively regulates starvation-induced autophagy by direct interaction with LC3. Noh HS, Hah YS, Zada S, Ha JH, Sim G, Hwang JS, Lai TH, Nguyen HQ, Park JY, Kim HJ, Byun JH, Hahm JR, Kang KR, Kim DR. Autophagy 12 2183-2196 (2016)
  14. Systematic analysis of ATG13 domain requirements for autophagy induction. Wallot-Hieke N, Verma N, Schlütermann D, Berleth N, Deitersen J, Böhler P, Stuhldreier F, Wu W, Seggewiß S, Peter C, Gohlke H, Mizushima N, Stork B. Autophagy 14 743-763 (2018)
  15. The ER-localized Ca2+-binding protein calreticulin couples ER stress to autophagy by associating with microtubule-associated protein 1A/1B light chain 3. Yang Y, Ma F, Liu Z, Su Q, Liu Y, Liu Z, Li Y. J Biol Chem 294 772-782 (2019)
  16. A helical LC3-interacting region mediates the interaction between the retroviral restriction factor Trim5α and mammalian autophagy-related ATG8 proteins. Keown JR, Black MM, Ferron A, Yap M, Barnett MJ, Pearce FG, Stoye JP, Goldstone DC. J Biol Chem 293 18378-18386 (2018)
  17. Lipidation-independent vacuolar functions of Atg8 rely on its noncanonical interaction with a vacuole membrane protein. Liu XM, Yamasaki A, Du XM, Coffman VC, Ohsumi Y, Nakatogawa H, Wu JQ, Noda NN, Du LL. Elife 7 e41237 (2018)
  18. An atypical LIR motif within UBA5 (ubiquitin like modifier activating enzyme 5) interacts with GABARAP proteins and mediates membrane localization of UBA5. Huber J, Obata M, Gruber J, Akutsu M, Löhr F, Rogova N, Güntert P, Dikic I, Kirkin V, Komatsu M, Dötsch V, Rogov VV. Autophagy 16 256-270 (2020)
  19. RACK1 mediates rewiring of intracellular networks induced by hepatitis C virus infection. Lee JS, Tabata K, Twu WI, Rahman MS, Kim HS, Yu JB, Jee MH, Bartenschlager R, Jang SK. PLoS Pathog 15 e1008021 (2019)
  20. Mutation-Structure-Function Relationship Based Integrated Strategy Reveals the Potential Impact of Deleterious Missense Mutations in Autophagy Related Proteins on Hepatocellular Carcinoma (HCC): A Comprehensive Informatics Approach. Awan FM, Obaid A, Ikram A, Janjua HA. Int J Mol Sci 18 E139 (2017)
  21. Dysregulation of autophagy in the central nervous system of sheep naturally infected with classical scrapie. López-Pérez Ó, Otero A, Filali H, Sanz-Rubio D, Toivonen JM, Zaragoza P, Badiola JJ, Bolea R, Martín-Burriel I. Sci Rep 9 1911 (2019)
  22. NBR1 is involved in selective pexophagy in filamentous ascomycetes and can be functionally replaced by a tagged version of its human homolog. Werner A, Herzog B, Voigt O, Valerius O, Braus GH, Pöggeler S. Autophagy 15 78-97 (2019)
  23. A novel conformation of the LC3-interacting region motif revealed by the structure of a complex between LC3B and RavZ. Kwon DH, Kim L, Kim BW, Kim JH, Roh KH, Choi EJ, Song HK. Biochem Biophys Res Commun 490 1093-1099 (2017)
  24. Autophagic degradation of KAT2A/GCN5 promotes directional migration of vascular smooth muscle cells by reducing TUBA/α-tubulin acetylation. Ouyang C, Mu J, Lu Q, Li J, Zhu H, Wang Q, Zou MH, Xie Z. Autophagy 16 1753-1770 (2020)
  25. Conformational Dynamics and Allostery in Pyruvate Kinase. Donovan KA, Zhu S, Liuni P, Peng F, Kessans SA, Wilson DJ, Dobson RC. J Biol Chem 291 9244-9256 (2016)
  26. Insights into links between autophagy and the ubiquitin system from the structure of LC3B bound to the LIR motif from the E3 ligase NEDD4. Qiu Y, Zheng Y, Wu KP, Schulman BA. Protein Sci 26 1674-1680 (2017)
  27. A small switch has a large effect on autophagy. Weissenhorn W, Fauvarque MO. Structure 22 1-2 (2014)
  28. Atg38-Atg8 interaction in fission yeast establishes a positive feedback loop to promote autophagy. Yu ZQ, Sun LL, Jiang ZD, Liu XM, Zhao D, Wang HT, He WZ, Dong MQ, Du LL. Autophagy 16 2036-2051 (2020)
  29. The conformational and mutational landscape of the ubiquitin-like marker for autophagosome formation in cancer. Fas BA, Maiani E, Sora V, Kumar M, Mashkoor M, Lambrughi M, Tiberti M, Papaleo E. Autophagy 17 2818-2841 (2021)
  30. Autophagy Correlates with the Therapeutic Responsiveness of Malignant Pleural Mesothelioma in 3D Models. Barbone D, Follo C, Echeverry N, Gerbaudo VH, Klabatsa A, Bueno R, Felley-Bosco E, Broaddus VC. PLoS One 10 e0134825 (2015)
  31. Characterization of a natural variant of human NDP52 and its functional consequences on mitophagy. Di Rita A, Angelini DF, Maiorino T, Caputo V, Cascella R, Kumar M, Tiberti M, Lambrughi M, Wesch N, Löhr F, Dötsch V, Carinci M, D'Acunzo P, Chiurchiù V, Papaleo E, Rogov VV, Giardina E, Battistini L, Strappazzon F. Cell Death Differ 28 2499-2516 (2021)
  32. Phosphorylation by casein kinase 2 enhances the interaction between ER-phagy receptor TEX264 and ATG8 proteins. Chino H, Yamasaki A, Ode KL, Ueda HR, Noda NN, Mizushima N. EMBO Rep 23 e54801 (2022)
  33. The basis for non-canonical ROK family function in the N-acetylmannosamine kinase from the pathogen Staphylococcus aureus. Coombes D, Davies JS, Newton-Vesty MC, Horne CR, Setty TG, Subramanian R, Moir JWB, Friemann R, Panjikar S, Griffin MDW, North RA, Dobson RCJ. J Biol Chem 295 3301-3315 (2020)
  34. Titanium Dioxide, but Not Zinc Oxide, Nanoparticles Cause Severe Transcriptomic Alterations in T98G Human Glioblastoma Cells. Fuster E, Candela H, Estévez J, Vilanova E, Sogorb MA. Int J Mol Sci 22 2084 (2021)
  35. Insights on autophagosome-lysosome tethering from structural and biochemical characterization of human autophagy factor EPG5. Nam SE, Cheung YWS, Nguyen TN, Gong M, Chan S, Lazarou M, Yip CK. Commun Biol 4 291 (2021)
  36. Solution structure of the autophagy-related protein LC3C reveals a polyproline II motif on a mobile tether with phosphorylation site. Krichel C, Möckel C, Schillinger O, Huesgen PF, Sticht H, Strodel B, Weiergräber OH, Willbold D, Neudecker P. Sci Rep 9 14167 (2019)
  37. Functional and solution structure studies of amino sugar deacetylase and deaminase enzymes from Staphylococcus aureus. Davies JS, Coombes D, Horne CR, Pearce FG, Friemann R, North RA, Dobson RCJ. FEBS Lett 593 52-66 (2019)
  38. Mechanistic insights into an atypical interaction between ATG8 and SH3P2 in Arabidopsis thaliana. Sun S, Feng L, Chung KP, Lee KM, Cheung HH, Luo M, Ren K, Law KC, Jiang L, Wong KB, Zhuang X. Autophagy 18 1350-1366 (2022)
  39. Focused Design of Novel Cyclic Peptides Endowed with GABARAP-Inhibiting Activity. Fassi EMA, Garofalo M, Sgrignani J, Dei Cas M, Mori M, Roda G, Cavalli A, Grazioso G. Int J Mol Sci 23 5070 (2022)
  40. Ablation of ZC3H11A causes early embryonic lethality and dysregulation of metabolic processes. Younis S, Jouneau A, Larsson M, Oudin JF, Adenot P, Omar J, Brochard V, Andersson L. Proc Natl Acad Sci U S A 120 e2216799120 (2023)
  41. Pharmacological Progress of Mitophagy Regulation. Sehgal SA, Wu H, Sajid M, Sohail S, Ahsan M, Parveen G, Riaz M, Khan MS, Iqbal MN, Malik A. Curr Neuropharmacol 21 1026-1041 (2023)
  42. Therapeutic Assay with the Non-toxic C-Terminal Fragment of Tetanus Toxin (TTC) in Transgenic Murine Models of Prion Disease. Betancor M, Moreno-Martínez L, López-Pérez Ó, Otero A, Hernaiz A, Barrio T, Badiola JJ, Osta R, Bolea R, Martín-Burriel I. Mol Neurobiol 58 5312-5326 (2021)
  43. A Fabry-Pérot cavity coupled surface plasmon photodiode for electrical biomolecular sensing. Allison G, Sana AK, Ogawa Y, Kato H, Ueno K, Misawa H, Hayashi K, Suzuki H. Nat Commun 12 6483 (2021)
  44. Atg8 family proteins, LIR/AIM motifs and other interaction modes. Rogov VV, Nezis IP, Tsapras P, Zhang H, Dagdas Y, Noda NN, Nakatogawa H, Wirth M, Mouilleron S, McEwan DG, Behrends C, Deretic V, Elazar Z, Tooze SA, Dikic I, Lamark T, Johansen T. Autophagy Rep 2 27694127.2023.2188523 (2023)
  45. Identification and Functional Characterization of Mutation in FYCO1 in Families with Congenital Cataract. Ullah MI, Rehman Z, Dad R, Alsrhani A, Shakil M, Ghanem HB, Alameen AAM, Elsadek MF, Eltayeb LB, Ullah S, Atif M. Life (Basel) 13 1788 (2023)
  46. Neuronal Gtf2i deletion alters mitochondrial and autophagic properties. Nir Sade A, Levy G, Schokoroy Trangle S, Elad Sfadia G, Bar E, Ophir O, Fischer I, Rokach M, Atzmon A, Parnas H, Rosenberg T, Marco A, Elroy Stein O, Barak B. Commun Biol 6 1269 (2023)
  47. Silencing of Tctex1 impairs autophagy lysosomal degradation of α-synuclein and cell viability. Zhang Y, Dong S, Liu Z, Ming J, Sun Z, Li X, Cai ZL, Li X. Neuroreport 29 385-392 (2018)