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Review

Structural biology of the Atg8 and Atg12 conjugation systems

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Article: 2277582 | Received 19 Sep 2023, Accepted 24 Oct 2023, Published online: 10 Nov 2023

References

  • Nakatogawa H. Mechanisms governing autophagosome biogenesis. Nat Rev Mol Cell Biol. 2020;21:439–17.
  • Ichimura Y, Kirisako T, Takao T, Satomi Y, Shimonishi Y, Ishihara N, Mizushima N, Tanida I, Kominami E, Ohsumi M et al. A ubiquitin-like system mediates protein lipidation. Nature. 2000;408:488–492.
  • Mizushima N, Noda T, Yoshimori T, Tanaka Y, Ishii T, George MD, Klionsky DJ, Ohsumi M and Ohsumi Y. A protein conjugation system essential for autophagy. Nature. 1998;395:395–398.
  • Hanada T, Noda NN, Satomi Y, Ichimura Y, Fujioka Y, Takao T, Inagaki F and Ohsumi Y. The Atg12-Atg5 conjugate has a novel E3-like activity for protein lipidation in autophagy. J Biol Chem. 2007;282:37298–37302.
  • Yamaguchi M, Noda NN, Yamamoto H, Shima T, Kumeta H, Kobashigawa Y, Akada R, Ohsumi Y and Inagaki F. Structural insights into Atg10-mediated formation of the autophagy-essential Atg12-Atg5 conjugate. Structure. 2012;20:1244–1254.
  • Kirisako T, Baba M, Ishihara N, Miyazawa K, Ohsumi M, Yoshimori T, Noda T and Ohsumi Y. Formation process of autophagosome is traced with Apg8/Aut7p in yeast. J Cell Biol. 1999;147:435–446.
  • Mizushima N, Yamamoto A, Hatano M, Kobayashi Y, Kabeya Y, Suzuki K, Tokuhisa T, Ohsumi Y and Yoshimori T. Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J Cell Biol. 2001;152:657–668.
  • Paz Y, Elazar Z and Fass D. Structure of GATE-16, membrane transport modulator and mammalian ortholog of autophagocytosis factor Aut7p. J Biol Chem. 2000;275:25445–25450.
  • Sugawara K, Suzuki NN, Fujioka Y, Mizushima N, Ohsumi Y and Inagaki F. The crystal structure of microtubule-associated protein light chain 3, a mammalian homologue of Saccharomyces cerevisiae Atg8. Genes Cells. 2004;9:611–618.
  • Knight D, Harris R, McAlister MS, Phelan JP, Geddes S, Moss SJ, Driscoll PC and Keep NH. The X-ray crystal structure and putative ligand-derived peptide binding properties of gamma-aminobutyric acid receptor type A receptor-associated protein. J Biol Chem. 2002;277:5556–5561.
  • Stangler T, Mayr LM and Willbold D. Solution structure of human GABA(A) receptor-associated protein GABARAP: implications for biological function and its regulation. J Biol Chem. 2002;277:13363–13366.
  • Bavro VN, Sola M, Bracher A, Kneussel M, Betz H and Weissenhorn W. Crystal structure of the GABA(A)-receptor-associated protein, GABARAP. EMBO Rep. 2002;3:183–189.
  • Coyle JE, Qamar S, Rajashankar KR and Nikolov DB. Structure of GABARAP in two conformations: implications for GABA(A) receptor localization and tubulin binding. Neuron. 2002;33:63–74.
  • Noda NN, Kumeta H, Nakatogawa H, Satoo K, Adachi W, Ishii J, Fujioka Y, Ohsumi Y and Inagaki F. Structural basis of target recognition by Atg8/LC3 during selective autophagy. Genes Cells. 2008;13:1211–1218.
  • Ma P, Mohrluder J, Schwarten M, Stoldt M, Singh SK, Hartmann R, Pacheco V and Willbold D. Preparation of a functional GABARAP-lipid conjugate in nanodiscs and its investigation by solution NMR spectroscopy. Chembiochem. 2010;11:1967–1970.
  • Maruyama T, Alam JM, Fukuda T, Kageyama S, Kirisako H, Ishii Y, Shimada I, Ohsumi Y, Komatsu M, Kanki T et al. Membrane perturbation by lipidated Atg8 underlies autophagosome biogenesis. Nat Struct Mol Biol. 2021;28:583–593.
  • Suzuki NN, Yoshimoto K, Fujioka Y, Ohsumi Y and Inagaki F. The crystal structure of plant ATG12 and its biological implication in autophagy. Autophagy. 2005;1:119–126.
  • Ichimura Y, Kumanomidou T, Sou YS, Mizushima T, Ezaki J, Ueno T, Kominami E, Yamane T, Tanaka K and Komatsu M. Structural basis for sorting mechanism of p62 in selective autophagy. J Biol Chem. 2008;283:22847–22857.
  • Scott SV, Guan J, Hutchins MU, Kim J and Klionsky DJ. Cvt19 is a receptor for the cytoplasm-to-vacuole targeting pathway. Mol Cell. 2001;7:1131–1141.
  • Bjorkoy G, Lamark T, Brech A, Outzen H, Perander M, Overvatn A, Stenmark H and Johansen T. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol. 2005;171:603–614.
  • Noda NN, Ohsumi Y and Inagaki F. Atg8-family interacting motif crucial for selective autophagy. FEBS Lett. 2010;584:1379–1385.
  • Birgisdottir AB, Lamark T and Johansen T. The LIR motif - crucial for selective autophagy. J Cell Sci. 2013;126:3237–3247.
  • Marshall RS, Hua Z, Mali S, McLoughlin F and Vierstra RD. ATG8-Binding UIM Proteins Define a New Class of Autophagy Adaptors and Receptors. Cell. 2019;177:766–781 e724.
  • Metlagel Z, Otomo C, Takaesu G and Otomo T. Structural basis of ATG3 recognition by the autophagic ubiquitin-like protein ATG12. Proc Natl Acad Sci USA. 2013;110:18844–18849.
  • Matoba K and Noda NN. Atg12-Interacting Motif Is Crucial for E2-E3 Interaction in Plant Atg8 System. Biol Pharm Bull. 2021;44:1337–1343.
  • Kumanomidou T, Mizushima T, Komatsu M, Suzuki A, Tanida I, Sou YS, Ueno T, Kominami E, Tanaka K and Yamane T. The crystal structure of human Atg4b, a processing and de-conjugating enzyme for autophagosome-forming modifiers. J Mol Biol. 2006;355:612–618.
  • Sugawara K, Suzuki NN, Fujioka Y, Mizushima N, Ohsumi Y and Inagaki F. Structural basis for the specificity and catalysis of human Atg4B responsible for mammalian autophagy. J Biol Chem. 2005;280:40058–40065.
  • Satoo K, Noda NN, Kumeta H, Fujioka Y, Mizushima N, Ohsumi Y and Inagaki F. The structure of Atg4B-LC3 complex reveals the mechanism of LC3 processing and delipidation during autophagy. EMBO J. 2009;28:1341–1350.
  • Skytte Rasmussen M, Mouilleron S, Kumar Shrestha B, Wirth M, Lee R, Bowitz Larsen K, Abudu Princely Y, O’Reilly N, Sjottem E, Tooze SA et al. ATG4B contains a C-terminal LIR motif important for binding and efficient cleavage of mammalian orthologs of yeast Atg8. Autophagy. 2017;13:834–853.
  • Choy A, Dancourt J, Mugo B, O’Connor TJ, Isberg RR, Melia TJ and Roy CR. The Legionella effector RavZ inhibits host autophagy through irreversible Atg8 deconjugation. Science. 2012;338:1072–1076.
  • Horenkamp FA, Kauffman KJ, Kohler LJ, Sherwood RK, Krueger KP, Shteyn V, Roy CR, Melia TJ and Reinisch KM. The Legionella Anti-autophagy Effector RavZ Targets the Autophagosome via PI3P- and Curvature-Sensing Motifs. Dev Cell. 2015;34:569–576.
  • Kwon DH, Kim S, Jung YO, Roh KH, Kim L, Kim BW, Hong SB, Lee IY, Song JH, Lee WC et al. The 1:2 complex between RavZ and LC3 reveals a mechanism for deconjugation of LC3 on the phagophore membrane. Autophagy. 2017;13:70–81.
  • Park SW, Jeon P, Yamasaki A, Lee HE, Choi H, Mun JY, Jun YW, Park JH, Lee SH, Lee SK et al. Development of new tools to study membrane-anchored mammalian Atg8 proteins. Autophagy. 2023;19:1424–1443.
  • Lee YK, Jun YW, Choi HE, Huh YH, Kaang BK, Jang DJ and Lee JA. Development of LC3/GABARAP sensors containing a LIR and a hydrophobic domain to monitor autophagy. EMBO J. 2017;36:1100–1116.
  • Yang A, Pantoom S and Wu YW. Elucidation of the anti-autophagy mechanism of the Legionella effector RavZ using semisynthetic LC3 proteins. Elife. 2017;6.
  • Komatsu M, Tanida I, Ueno T, Ohsumi M, Ohsumi Y and Kominami E. The C-terminal region of an Apg7p/Cvt2p is required for homodimerization and is essential for its E1 activity and E1-E2 complex formation. J Biol Chem. 2001;276:9846–9854.
  • Noda NN, Satoo K, Fujioka Y, Kumeta H, Ogura K, Nakatogawa H, Ohsumi Y and Inagaki F. Structural basis of Atg8 activation by a homodimeric E1, Atg7. Mol Cell. 2011;44:462–475.
  • Taherbhoy AM, Tait SW, Kaiser SE, Williams AH, Deng A, Nourse A, Hammel M, Kurinov I, Rock CO, Green DR et al. Atg8 transfer from Atg7 to Atg3: a distinctive E1-E2 architecture and mechanism in the autophagy pathway. Mol Cell. 2011;44:451–461.
  • Hong SB, Kim BW, Lee KE, Kim SW, Jeon H, Kim J and Song HK. Insights into noncanonical E1 enzyme activation from the structure of autophagic E1 Atg7 with Atg8. Nat Struct Mol Biol. 2011;18:1323–1330.
  • Yamaguchi M, Satoo K, Suzuki H, Fujioka Y, Ohsumi Y, Inagaki F and Noda NN. Atg7 Activates an Autophagy-Essential Ubiquitin-like Protein Atg8 through Multi-Step Recognition. J Mol Biol. 2018;430:249–257.
  • Yamaguchi M, Matoba K, Sawada R, Fujioka Y, Nakatogawa H, Yamamoto H, Kobashigawa Y, Hoshida H, Akada R, Ohsumi Y et al. Noncanonical recognition and UBL loading of distinct E2s by autophagy-essential Atg7. Nat Struct Mol Biol. 2012;19:1250–1256.
  • Kaiser SE, Mao K, Taherbhoy AM, Yu S, Olszewski JL, Duda DM, Kurinov I, Deng A, Fenn TD, Klionsky DJ et al. Noncanonical E2 recruitment by the autophagy E1 revealed by Atg7-Atg3 and Atg7-Atg10 structures. Nat Struct Mol Biol. 2012;19:1242–1249.
  • Yamada Y, Suzuki NN, Hanada T, Ichimura Y, Kumeta H, Fujioka Y, Ohsumi Y and Inagaki F. The crystal structure of Atg3, an autophagy-related ubiquitin carrier protein (E2) enzyme that mediates Atg8 lipidation. J Biol Chem. 2007;282:8036–8043.
  • Hanada T, Satomi Y, Takao T and Ohsumi Y. The amino-terminal region of Atg3 is essential for association with phosphatidylethanolamine in Atg8 lipidation. FEBS Lett. 2009;583:1078–1083.
  • Nishimura T, Lazzeri G, Mizushima N, Covino R and Tooze SA. Unique amphipathic alpha helix drives membrane insertion and enzymatic activity of ATG3. Sci Adv. 2023;9:eadh1281.
  • Nath S, Dancourt J, Shteyn V, Puente G, Fong WM, Nag S, Bewersdorf J, Yamamoto A, Antonny B and Melia TJ. Lipidation of the LC3/GABARAP family of autophagy proteins relies on a membrane-curvature-sensing domain in Atg3. Nat Cell Biol. 2014;16:415–424.
  • Hong SB, Kim BW, Kim JH and Song HK. Structure of the autophagic E2 enzyme Atg10. Acta Crystallogr D Biol Crystallogr. 2012;68:1409–1417.
  • Matsushita M, Suzuki NN, Obara K, Fujioka Y, Ohsumi Y and Inagaki F. Structure of Atg5.Atg16, a complex essential for autophagy. J Biol Chem. 2007;282:6763–6772.
  • Fujioka Y, Noda NN, Nakatogawa H, Ohsumi Y and Inagaki F. Dimeric coiled-coil structure of Saccharomyces cerevisiae Atg16 and its functional significance in autophagy. J Biol Chem. 2010;285:1508–1515.
  • Munzel L, Neumann P, Otto FB, Krick R, Metje-Sprink J, Kroppen B, Karedla N, Enderlein J, Meinecke M, Ficner R et al. Atg21 organizes Atg8 lipidation at the contact of the vacuole with the phagophore. Autophagy. 2021;17:1458–1478.
  • Noda NN, Fujioka Y, Hanada T, Ohsumi Y and Inagaki F. Structure of the Atg12-Atg5 conjugate reveals a platform for stimulating Atg8-PE conjugation. EMBO Rep. 2013;14:206–211.
  • Otomo C, Metlagel Z, Takaesu G and Otomo T. Structure of the human ATG12~ATG5 conjugate required for LC3 lipidation in autophagy. Nat Struct Mol Biol. 2013;20:59–66.
  • Pang Y, Yamamoto H, Sakamoto H, Oku M, Mutungi JK, Sahani MH, Kurikawa Y, Kita K, Noda NN, Sakai Y et al. Evolution from covalent conjugation to non-covalent interaction in the ubiquitin-like ATG12 system. Nat Struct Mol Biol. 2019;26:289–296.
  • Chen D, Fan W, Lu Y, Ding X, Chen S and Zhong Q. A mammalian autophagosome maturation mechanism mediated by TECPR1 and the Atg12-Atg5 conjugate. Mol Cell. 2012;45:629–641.
  • Kim JH, Hong SB, Lee JK, Han S, Roh KH, Lee KE, Kim YK, Choi EJ and Song HK. Insights into autophagosome maturation revealed by the structures of ATG5 with its interacting partners. Autophagy. 2015;11:75–87.
  • Wang Y, Jefferson M, Whelband M, Kreuzer K, Mccoll J, Verkade P, Mayer U and Wileman T. TECPR1 provides E3-ligase like activity to the ATG5-ATG12 complex to conjugate LC3/ATG8 to damaged lysosomes. bioRxiv. 2023.
  • Sakoh-Nakatogawa M, Matoba K, Asai E, Kirisako H, Ishii J, Noda NN, Inagaki F, Nakatogawa H and Ohsumi Y. Atg12-Atg5 conjugate enhances E2 activity of Atg3 by rearranging its catalytic site. Nat Struct Mol Biol. 2013;20:433–439.
  • Zheng Y, Qiu Y, Grace CRR, Liu X, Klionsky DJ and Schulman BA. A switch element in the autophagy E2 Atg3 mediates allosteric regulation across the lipidation cascade. Nat Commun. 2019;10:3600.
  • Romanov J, Walczak M, Ibiricu I, Schuchner S, Ogris E, Kraft C and Martens S. Mechanism and functions of membrane binding by the Atg5-Atg12/Atg16 complex during autophagosome formation. EMBO J. 2012;31:4304–4317.
  • Dooley HC, Razi M, Polson HE, Girardin SE, Wilson MI and Tooze SA. WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5-16L1. Mol Cell. 2014;55:238–252.
  • Juris L, Montino M, Rube P, Schlotterhose P, Thumm M and Krick R. PI3P binding by Atg21 organises Atg8 lipidation. EMBO J. 2015;34:955–973.
  • Gong X, Wang Y, Tang Y, Wang Y, Zhang M, Li M, Zhang Y and Pan L. ATG16L1 adopts a dual-binding site mode to interact with WIPI2b in autophagy. Sci Adv. 2023;9:eadf0824.
  • Strong LM, Chang C, Riley JF, Boecker CA, Flower TG, Buffalo CZ, Ren X, Stavoe AK, Holzbaur EL and Hurley JH. Structural basis for membrane recruitment of ATG16L1 by WIPI2 in autophagy. Elife. 2021;10.
  • Pantoom S, Konstantinidis G, Voss S, Han H, Hofnagel O, Li Z and Wu YW. RAB33B recruits the ATG16L1 complex to the phagophore via a noncanonical RAB binding protein. Autophagy. 2021;17:2290–2304.
  • Metje-Sprink J, Groffmann J, Neumann P, Barg-Kues B, Ficner R, Kuhnel K, Schalk AM and Binotti B. Crystal structure of the Rab33B/Atg16L1 effector complex. Sci Rep. 2020;10:12956.
  • Kirkin V and Rogov VV. A Diversity of Selective Autophagy Receptors Determines the Specificity of the Autophagy Pathway. Mol Cell. 2019;76:268–285.
  • Nakatogawa H, Ichimura Y and Ohsumi Y. Atg8, a ubiquitin-like protein required for autophagosome formation, mediates membrane tethering and hemifusion. Cell. 2007;130:165–178.
  • Weidberg H, Shpilka T, Shvets E, Abada A, Shimron F and Elazar Z. LC3 and GATE-16 N termini mediate membrane fusion processes required for autophagosome biogenesis. Dev Cell. 2011;20:444–454.
  • Knorr RL, Nakatogawa H, Ohsumi Y, Lipowsky R, Baumgart T and Dimova R. Membrane morphology is actively transformed by covalent binding of the protein Atg8 to PE-lipids. PLoS One. 2014;9:e115357.
  • Wu F, Watanabe Y, Guo XY, Qi X, Wang P, Zhao HY, Wang Z, Fujioka Y, Zhang H, Ren JQ et al. Structural Basis of the Differential Function of the Two C. elegans Atg8 Homologs, LGG-1 and LGG-2, in Autophagy. Mol Cell. 2015;60:914–929.
  • Kaufmann A, Beier V, Franquelim HG and Wollert T. Molecular mechanism of autophagic membrane-scaffold assembly and disassembly. Cell. 2014;156:469–481.