Structural biology of the core autophagy machinery

Current Opinion in Structural Biology

Volumn 43, Issue , 2017, Pages 10-17

  Suzuki, Hironori ^a   Osawa, Takuo ^a   Fujioka, Yuko ^a   Noda, Nobuo N ^a  

^a INSTITUTE OF MICROBIAL CHEMISTRY   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

AUTOPHAGY RELATED PROTEIN; AUTOPHAGY RELATED PROTEIN 101; AUTOPHAGY RELATED PROTEIN 12; AUTOPHAGY RELATED PROTEIN 13; AUTOPHAGY RELATED PROTEIN 137; AUTOPHAGY RELATED PROTEIN 14; AUTOPHAGY RELATED PROTEIN 17; AUTOPHAGY RELATED PROTEIN 170; AUTOPHAGY RELATED PROTEIN 18; AUTOPHAGY RELATED PROTEIN 2; AUTOPHAGY RELATED PROTEIN 29; AUTOPHAGY RELATED PROTEIN 31; AUTOPHAGY RELATED PROTEIN 5; AUTOPHAGY RELATED PROTEIN 8; AUTOPHAGY RELATED PROTEIN 9; BECLIN 1; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MICROTUBULE ASSOCIATED PROTEIN 1; MICROTUBULE ASSOCIATED PROTEIN 2; PHOSPHATIDYLINOSITOL 3 KINASE; UBIQUITIN PROTEIN LIGASE E3; UNCLASSIFIED DRUG;

AMINO TERMINAL SEQUENCE; AUTOPHAGOSOME; AUTOPHAGY; BINDING AFFINITY; CARBOXY TERMINAL SEQUENCE; CONFORMATIONAL TRANSITION; HUMAN; MOLECULAR EVOLUTION; NONHUMAN; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN MOTIF; PROTEIN PROTEIN INTERACTION; PROTEIN STRUCTURE; REGULATORY MECHANISM; REVIEW; ANIMAL; METABOLISM;

ANIMALS; AUTOPHAGY; AUTOPHAGY-RELATED PROTEINS; HUMANS; PHOSPHATIDYLINOSITOL 3-KINASES;

EID: 85007557293     PISSN: 0959440X     EISSN: 1879033X     Source Type: Journal    
DOI: 10.1016/j.sbi.2016.09.010     Document Type: Review

References (63)

1. 1 Mizushima, N., Komatsu, M., Autophagy: renovation of cells and tissues. Cell 147 (2011), 728–741.
2. 2 Mizushima, N., Yoshimori, T., Ohsumi, Y., The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol 27 (2011), 107–132.
3. 3 Suzuki, K., Ohsumi, Y., Current knowledge of the pre-autophagosomal structure (PAS). FEBS Lett 584 (2010), 1280–1286.
4. 4 Noda, N.N., Ohsumi, Y., Inagaki, F., ATG systems from the protein structural point of view. Chem Rev 109 (2009), 1587–1598.
5. 5 Klionsky, D.J., Schulman, B.A., Dynamic regulation of macroautophagy by distinctive ubiquitin-like proteins. Nat Struct Mol Biol 21 (2014), 336–345.
6. 6 Noda, N.N., Inagaki, F., Mechanisms of autophagy. Annu Rev Biophys 44 (2015), 101–122.
7. 7 Hurley, J.H., Schulman, B.A., Atomistic autophagy: the structures of cellular self-digestion. Cell 157 (2014), 300–311.
8. 8• Young, L.N., Cho, K., Lawrence, R., Zoncu, R., Hurley, J.H., Dynamics and architecture of the NRBF2-containing phosphatidylinositol 3-kinase complex I of autophagy. Proc Natl Acad Sci U S A, 2016, 10.1073/pnas.1603650113 This study for the first time describes the architecture of the pentameric PI3K complex I and establishes the molecular role of the most recently identified component, Atg38/NRBF2.
9. 9 Noda, N.N., Fujioka, Y., Atg1 family kinases in autophagy initiation. Cell Mol Life Sci 72 (2015), 3083–3096.
10. 10 Lin, M.G., Hurley, J.H., Structure and function of the ULK1 complex in autophagy. Curr Opin Cell Biol 39 (2016), 61–68.
11. 11•• Fujioka, Y., Suzuki, S.W., Yamamoto, H., Kondo-Kakuta, C., Kimura, Y., Hirano, H., Akada, R., Inagaki, F., Ohsumi, Y., Noda, N.N., Structural basis of starvation-induced assembly of the autophagy initiation complex. Nat Struct Mol Biol 21 (2014), 513–521 This study establishes the critical interactions constructing the autophagy initiation complex by X-ray crystallography, and in combination with LC–MS/MS and cell biological studies, reveal the molecular mechanism of starvation-induced assembly of the autophagy initiation complex.
12. 12 Stjepanovic, G., Davies, C.W., Stanley, R.E., Ragusa, M.J., Kim do, J., Hurley, J.H., Assembly and dynamics of the autophagy-initiating Atg1 complex. Proc Natl Acad Sci U S A 111 (2014), 12793–12798.
13. 13 Jao, C.C., Ragusa, M.J., Stanley, R.E., Hurley, J.H., A HORMA domain in Atg13 mediates PI 3-kinase recruitment in autophagy. Proc Natl Acad Sci U S A 110 (2013), 5486–5491.
14. 14• Yamamoto, H., Fujioka, Y., Suzuki, S.W., Noshiro, D., Suzuki, H., Kondo-Kakuta, C., Kimura, Y., Hirano, H., Ando, T., Noda, N.N., et al. The intrinsically disordered protein Atg13 mediates supramolecular assembly of autophagy initiation complexes. Dev Cell 38 (2016), 86–99 Combination of structural biological, biochemical and cell biological studies reveals the molecular mechanism of supramolecular assembly of the autophagy initiation complexes that functions as the core of the PAS.
15. 15 Ragusa, M.J., Stanley, R.E., Hurley, J.H., Architecture of the Atg17 complex as a scaffold for autophagosome biogenesis. Cell 151 (2012), 1501–1512.
16. 16 Kabeya, Y., Noda, N.N., Fujioka, Y., Suzuki, K., Inagaki, F., Ohsumi, Y., Characterization of the Atg17–Atg29–Atg31 complex specifically required for starvation-induced autophagy in Saccharomyces cerevisiae. Biochem Biophys Res Commun 389 (2009), 612–615.
17. 17 Kamada, Y., Funakoshi, T., Shintani, T., Nagano, K., Ohsumi, M., Ohsumi, Y., Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J Cell Biol 150 (2000), 1507–1513.
18. 18 Kofinger, J., Ragusa, M.J., Lee, I.H., Hummer, G., Hurley, J.H., Solution structure of the Atg1 complex: implications for the architecture of the phagophore assembly site. Structure 23 (2015), 809–818.
19. 19 Geng, J., Baba, M., Nair, U., Klionsky, D.J., Quantitative analysis of autophagy-related protein stoichiometry by fluorescence microscopy. J Cell Biol 182 (2008), 129–140.
20. 20 Mizushima, N., The role of the Atg1/ULK1 complex in autophagy regulation. Curr Opin Cell Biol 22 (2010), 132–139.
21. 21 Noda, N.N., Mizushima, N., Atg101: not just an accessory subunit in the autophagy-initiation complex. Cell Struct Funct 41 (2016), 13–20.
22. 22 Chew, L.H., Lu, S., Liu, X., Li, F.K., Yu, A.Y., Klionsky, D.J., Dong, M.Q., Yip, C.K., Molecular interactions of the Saccharomyces cerevisiae Atg1 complex provide insights into assembly and regulatory mechanisms. Autophagy 11 (2015), 891–905.
23. 23 Lazarus, M.B., Shokat, K.M., Discovery and structure of a new inhibitor scaffold of the autophagy initiating kinase ULK1. Bioorg Med Chem 23 (2015), 5483–5488.
24. 24 Li, F., Chung, T., Vierstra, R.D., AUTOPHAGY-RELATED11 plays a critical role in general autophagy- and senescence-induced mitophagy in Arabidopsis. Plant Cell 26 (2014), 788–807.
25. 25 Michel, M., Schwarten, M., Decker, C., Nagel-Steger, L., Willbold, D., Weiergraber, O.H., The mammalian autophagy initiator complex contains 2 HORMA domain proteins. Autophagy 11 (2015), 2300–2308.
26. 26• Suzuki, H., Kaizuka, T., Mizushima, N., Noda, N.N., Structure of the Atg101–Atg13 complex reveals essential roles of Atg101 in autophagy initiation. Nat Struct Mol Biol 22 (2015), 572–580 This study for the first time reveals the structure of Atg101 and establishes two critical roles of Atg101: stabilizing Atg13 and recruiting downstream autophagy factors using newly identified WF finger.
27. 27 Qi, S., Kim do, J., Stjepanovic, G., Hurley, J.H., Structure of the human Atg13–Atg101 HORMA heterodimer: an interaction hub within the ULK1 complex. Structure 23 (2015), 1848–1857.
28. 28 Suzuki, S.W., Yamamoto, H., Oikawa, Y., Kondo-Kakuta, C., Kimura, Y., Hirano, H., Ohsumi, Y., Atg13 HORMA domain recruits Atg9 vesicles during autophagosome formation. Proc Natl Acad Sci U S A 112 (2015), 3350–3355.
29. 29 Araki, Y., Ku, W.C., Akioka, M., May, A.I., Hayashi, Y., Arisaka, F., Ishihama, Y., Ohsumi, Y., Atg38 is required for autophagy-specific phosphatidylinositol 3-kinase complex integrity. J Cell Biol 203 (2013), 299–313.
30. 30•• Baskaran, S., Carlson, L.A., Stjepanovic, G., Young, L.N., Kim do, J., Grob, P., Stanley, R.E., Nogales, E., Hurley, J.H., Architecture and dynamics of the autophagic phosphatidylinositol 3-kinase complex. Elife, 3, 2014 This study for the first time reveals the overall V-shaped architecture of tetrameric PI3K complex I at low resolution, which can be a structural basis for studying the molecular functions of this huge protein complex.
31. 31 Noda, N.N., Kobayashi, T., Adachi, W., Fujioka, Y., Ohsumi, Y., Inagaki, F., Structure of the novel C-terminal domain of vacuolar protein sorting 30/autophagy-related protein 6 and its specific role in autophagy. J Biol Chem 287 (2012), 16256–16266.
32. 32 Fan, W., Nassiri, A., Zhong, Q., Autophagosome targeting and membrane curvature sensing by Barkor/Atg14(L). Proc Natl Acad Sci U S A 108 (2011), 7769–7774.
33. 33 Levine, B., Liu, R., Dong, X., Zhong, Q., Beclin orthologs: integrative hubs of cell signaling, membrane trafficking, and physiology. Trends Cell Biol 25 (2015), 533–544.
34. 34•• Rostislavleva, K., Soler, N., Ohashi, Y., Zhang, L., Pardon, E., Burke, J.E., Masson, G.R., Johnson, C., Steyaert, J., Ktistakis, N.T., et al. Structure and flexibility of the endosomal Vps34 complex reveals the basis of its function on membranes. Science, 350, 2015, aac7365 This study for the first time reveals the crystal structure of PI3K complex II and unambiguously shows the domain arrangement and domain–domain interactions in the huge protein complex, which can also be a structural basis for the PI3K complex I.
35. 35 Otomo, C., Metlagel, Z., Takaesu, G., Otomo, T., Structure of the human ATG12∼ATG5 conjugate required for LC3 lipidation in autophagy. Nat Struct Mol Biol 20 (2013), 59–66.
36. 36 Noda, N.N., Fujioka, Y., Hanada, T., Ohsumi, Y., Inagaki, F., Structure of the Atg12–Atg5 conjugate reveals a platform for stimulating Atg8–PE conjugation. EMBO Rep 14 (2013), 206–211.
37. 37 Hanada, T., Noda, N.N., Satomi, Y., Ichimura, Y., Fujioka, Y., Takao, T., Inagaki, F., Ohsumi, Y., The Atg12–Atg5 conjugate has a novel E3-like activity for protein lipidation in autophagy. J Biol Chem 282 (2007), 37298–37302.
38. 38 Sakoh-Nakatogawa, M., Matoba, K., Asai, E., Kirisako, H., Ishii, J., Noda, N.N., Inagaki, F., Nakatogawa, H., Ohsumi, Y., Atg12–Atg5 conjugate enhances E2 activity of Atg3 by rearranging its catalytic site. Nat Struct Mol Biol 20 (2013), 433–439.
39. 39 Metlagel, Z., Otomo, C., Takaesu, G., Otomo, T., Structural basis of ATG3 recognition by the autophagic ubiquitin-like protein ATG12. Proc Natl Acad Sci U S A 110 (2013), 18844–18849.
40. 40 Fujioka, Y., Noda, N.N., Nakatogawa, H., Ohsumi, Y., Inagaki, F., Dimeric coiled-coil structure of Saccharomyces cerevisiae Atg16 and its functional significance in autophagy. J Biol Chem 285 (2010), 1508–1515.
41. 41 Fujita, N., Itoh, T., Omori, H., Fukuda, M., Noda, T., Yoshimori, T., The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. Mol Biol Cell 19 (2008), 2092–2100.
42. 42 Romanov, J., Walczak, M., Ibiricu, I., Schuchner, S., Ogris, E., Kraft, C., Martens, S., Mechanism and functions of membrane binding by the Atg5–Atg12/Atg16 complex during autophagosome formation. EMBO J 31 (2012), 4304–4317.
43. 43 Kaufmann, A., Beier, V., Franquelim, H.G., Wollert, T., Molecular mechanism of autophagic membrane-scaffold assembly and disassembly. Cell 156 (2014), 469–481.
44. 44 Noda, N.N., Ohsumi, Y., Inagaki, F., Atg8-family interacting motif crucial for selective autophagy. FEBS Lett 584 (2010), 1379–1385.
45. 45 Birgisdottir, A.B., Lamark, T., Johansen, T., The LIR motif — crucial for selective autophagy. J Cell Sci 126 (2013), 3237–3247.
46. 46 Ge, L., Zhang, M., Schekman, R., Phosphatidylinositol 3-kinase and COPII generate LC3 lipidation vesicles from the ER–Golgi intermediate compartment. Elife, 3, 2014, e04135.
47. 47 Ge, L., Melville, D., Zhang, M., Schekman, R., The ER–Golgi intermediate compartment is a key membrane source for the LC3 lipidation step of autophagosome biogenesis. Elife, 2, 2013, e00947.
48. 48 Sakoh-Nakatogawa, M., Kirisako, H., Nakatogawa, H., Ohsumi, Y., Localization of Atg3 to autophagy-related membranes and its enhancement by the Atg8-family interacting motif to promote expansion of the membranes. FEBS Lett 589 (2015), 744–749.
49. 49 Ngu, M., Hirata, E., Suzuki, K., Visualization of Atg3 during autophagosome formation in Saccharomyces cerevisiae. J Biol Chem 290 (2015), 8146–8153.
50. 50 Nakatogawa, H., Ichimura, Y., Ohsumi, Y., Atg8, a ubiquitin-like protein required for autophagosome formation, mediates membrane tethering and hemifusion. Cell 130 (2007), 165–178.
51. 51 Weidberg, H., Shpilka, T., Shvets, E., Abada, A., Shimron, F., Elazar, Z., LC3 and GATE-16 N termini mediate membrane fusion processes required for autophagosome biogenesis. Dev Cell 20 (2011), 444–454.
52. 52 Wu, F., Watanabe, Y., Guo, X.Y., Qi, X., Wang, P., Zhao, H.Y., Wang, Z., Fujioka, Y., Zhang, H., Ren, J.Q., et al. structural basis of the differential function of the two C. elegans Atg8 homologs, LGG-1 and LGG-2, in autophagy. Mol Cell 60 (2015), 914–929.
53. 53 Yamamoto, H., Kakuta, S., Watanabe, T.M., Kitamura, A., Sekito, T., Kondo-Kakuta, C., Ichikawa, R., Kinjo, M., Ohsumi, Y., Atg9 vesicles are an important membrane source during early steps of autophagosome formation. J Cell Biol 198 (2012), 219–233.
54. 54 Papinski, D., Schuschnig, M., Reiter, W., Wilhelm, L., Barnes, C.A., Maiolica, A., Hansmann, I., Pfaffenwimmer, T., Kijanska, M., Stoffel, I., et al. Early steps in autophagy depend on direct phosphorylation of Atg9 by the Atg1 kinase. Mol Cell 53 (2014), 471–483.
55. 55 Rao, Y., Perna, M.G., Hofmann, B., Beier, V., Wollert, T., The Atg1-kinase complex tethers Atg9-vesicles to initiate autophagy. Nat Commun, 7, 2016, 10338.
56. 56 Velikkakath, A.K., Nishimura, T., Oita, E., Ishihara, N., Mizushima, N., Mammalian Atg2 proteins are essential for autophagosome formation and important for regulation of size and distribution of lipid droplets. Mol Biol Cell 23 (2012), 896–909.
57. 57 Watanabe, Y., Kobayashi, T., Yamamoto, H., Hoshida, H., Akada, R., Inagaki, F., Ohsumi, Y., Noda, N.N., Structure-based analyses reveal distinct binding sites for Atg2 and phosphoinositides in Atg18. J Biol Chem 287 (2012), 31681–31690.
58. 58 Baskaran, S., Ragusa, M.J., Boura, E., Hurley, J.H., Two-site recognition of phosphatidylinositol 3-phosphate by PROPPINs in autophagy. Mol Cell 47 (2012), 339–348.
59. 59 Krick, R., Busse, R.A., Scacioc, A., Stephan, M., Janshoff, A., Thumm, M., Kuhnel, K., Structural and functional characterization of the two phosphoinositide binding sites of PROPPINs, a beta-propeller protein family. Proc Natl Acad Sci U S A 109 (2012), E2042–E2049.
60. 60 Rieter, E., Vinke, F., Bakula, D., Cebollero, E., Ungermann, C., Proikas-Cezanne, T., Reggiori, F., Atg18 function in autophagy is regulated by specific sites within its beta-propeller. J Cell Sci 126 (2013), 593–604.
61. 61 Suzuki, K., Akioka, M., Kondo-Kakuta, C., Yamamoto, H., Ohsumi, Y., Fine mapping of autophagy-related proteins during autophagosome formation in Saccharomyces cerevisiae. J Cell Sci 126 (2013), 2534–2544.
62. 62 McNicholas, S., Potterton, E., Wilson, K.S., Noble, M.E., Presenting your structures: the CCP 4 mg molecular-graphics software. Acta Crystallogr D Biol Crystallogr 67 (2011), 386–394.
63. 63 Y. Ohashi, N. Soler, M. García Ortegón, L. Zhang, M.L. Kirsten, O. Perisic, G.R. Masson, J.E. Burke, A.J. Jakobi, A.A. Apostolakis et al.: Characterization of Atg38 and NRBF2, a fifth subunit of the autophagic Vps34/PIK3C3 complex, Autophagy in press.