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Yoshinori Ohsumi – One of the best experts on this subject based on the ideXlab platform.

  • Atg9 is a lipid scramblase that mediates autophagosomal membrane expansion
    Nature Structural & Molecular Biology, 2020
    Co-Authors: Kazuaki Matoba, Daisuke Noshiro, Tetsuya Kotani, Akihisa Tsutsumi, Takuma Tsuji, Takaharu Mori, Yuji Sugita, Norimichi Nomura, So Iwata, Yoshinori Ohsumi

    Abstract:

    The molecular function of Atg9, the sole transmembrane protein in the autophagosome-forming machinery, remains unknown. Atg9 colocalizes with Atg2 at the expanding edge of the isolation membrane (IM), where Atg2 receives phospholipids from the endoplasmic reticulum (ER). Here we report that yeast and human Atg9 are lipid scramblases that translocate phospholipids between outer and inner leaflets of liposomes in vitro. Cryo-EM of fission yeast Atg9 reveals a homotrimer, with two connected pores forming a path between the two membrane leaflets: one pore, located at a protomer, opens laterally to the cytoplasmic leaflet; the other, at the trimer center, traverses the membrane vertically. Mutation of residues lining the pores impaired IM expansion and autophagy activity in yeast and abolished Atg9’s ability to transport phospholipids between liposome leaflets. These results suggest that phospholipids delivered by Atg2 are translocated from the cytoplasmic to the luminal leaflet by Atg9, thereby driving autophagosomal membrane expansion. Cryo-EM and liposome assays reveal that Atg9 functions as a lipid scramblase, transporting phospholipids between inner and outer liposome leaflets. Analyses of mutants in yeast support a role for this activity in autophagy.

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  • Two distinct mechanisms target the autophagy-related E3 complex to the pre-autophagosomal structure.
    eLife, 2019
    Co-Authors: Kumi Harada, Hayashi Yamamoto, Yayoi Kimura, Hisashi Hirano, Tetsuya Kotani, Hiromi Kirisako, Machiko Sakoh-nakatogawa, Yu Oikawa, Yoshinori Ohsumi, Hitoshi Nakatogawa

    Abstract:

    In autophagy, Atg proteins organize the pre-autophagosomal structure (PAS) to initiate autophagosome formation. Previous studies in yeast revealed that the autophagy-related E3 complex Atg12-Atg5-Atg16 is recruited to the PAS via Atg16 interaction with Atg21, which binds phosphatidylinositol 3-phosphate (PI3P) produced at the PAS, to stimulate conjugation of the ubiquitin-like protein Atg8 to phosphatidylethanolamine. Here, we discover a novel mechanism for the PAS targeting of Atg12-Atg5-Atg16, which is mediated by the interaction of Atg12 with the Atg1 kinase complex that serves as a scaffold for PAS organization. While autophagy is partially defective without one of these mechanisms, cells lacking both completely lose the PAS localization of Atg12-Atg5-Atg16 and show no autophagic activity. As with the PI3P-dependent mechanism, Atg12-Atg5-Atg16 recruited via the Atg12-dependent mechanism stimulates Atg8 lipidation, but also has the specific function of facilitating PAS scaffold assembly. Thus, this study significantly advances our understanding of the nucleation step in autophagosome formation.

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  • ATG7 Activates an Autophagy-Essential Ubiquitin-like Protein Atg8 through Multi-Step Recognition.
    Journal of Molecular Biology, 2018
    Co-Authors: Masaya Yamaguchi, Yuko Fujioka, Hironori Suzuki, Yoshinori Ohsumi, Fuyuhiko Inagaki, Kenji Satoo, Nobuo N. Noda

    Abstract:

    Atg8 is a unique ubiquitin-like protein that is covalently conjugated with a phosphatidylethanolamine through reactions similar to ubiquitination and plays essential roles in autophagy. ATG7 is the E1 enzyme for Atg8, and it activates the C-terminal Gly116 of Atg8 using ATP. Here, we report the crystal structure of Atg8 bound to the C-terminal domain of ATG7 in an unprecedented mode. Atg8 neither contacts with the central β-sheet nor binds to the catalytic site of ATG7, both of which were observed in previously reported ATG7-Atg8 structures. Instead, Atg8 binds to the C-terminal α-helix and crossover loop, thereby changing the autoinhibited conformation of the crossover loop observed in the free ATG7 structure into a short helix and a disordered loop. Mutational analyses suggested that this interaction mode is important for the activation reaction. We propose that ATG7 recognizes Atg8 through multiple steps, which would be necessary to induce a conformational change in ATG7 that is optimal for the activation reaction.

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Fuyuhiko Inagaki – One of the best experts on this subject based on the ideXlab platform.

  • ATG7 Activates an Autophagy-Essential Ubiquitin-like Protein Atg8 through Multi-Step Recognition.
    Journal of Molecular Biology, 2018
    Co-Authors: Masaya Yamaguchi, Yuko Fujioka, Hironori Suzuki, Yoshinori Ohsumi, Fuyuhiko Inagaki, Kenji Satoo, Nobuo N. Noda

    Abstract:

    Atg8 is a unique ubiquitin-like protein that is covalently conjugated with a phosphatidylethanolamine through reactions similar to ubiquitination and plays essential roles in autophagy. ATG7 is the E1 enzyme for Atg8, and it activates the C-terminal Gly116 of Atg8 using ATP. Here, we report the crystal structure of Atg8 bound to the C-terminal domain of ATG7 in an unprecedented mode. Atg8 neither contacts with the central β-sheet nor binds to the catalytic site of ATG7, both of which were observed in previously reported ATG7-Atg8 structures. Instead, Atg8 binds to the C-terminal α-helix and crossover loop, thereby changing the autoinhibited conformation of the crossover loop observed in the free ATG7 structure into a short helix and a disordered loop. Mutational analyses suggested that this interaction mode is important for the activation reaction. We propose that ATG7 recognizes Atg8 through multiple steps, which would be necessary to induce a conformational change in ATG7 that is optimal for the activation reaction.

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  • architecture of the atg12 atg5 atg16 complex and its molecular role in autophagy
    Autophagy: Cancer Other Pathologies Inflammation Immunity Infection and Aging#R##N#Volume 3 – Mitophagy, 2014
    Co-Authors: Nobuo N. Noda, Fuyuhiko Inagaki

    Abstract:

    Atg5 is covalently modified with Atg12 via reactions that are similar to ubiquitination, and it noncovalently interacts with Atg16. Formation of the Atg12–Atg5–Atg16 complex is essential for its E3-like function: facilitation of Atg8 transfer from Atg3 to phosphatidylethanolamine at autophagic membranes. Structural studies on the Atg12–Atg5–Atg16 complex revealed that the unique architecture of this protein complex is totally distinct from the other E3 enzymes. The Atg12–Atg5–Atg16 complex interacts directly with Atg3 via Atg12, and enhances the conjugase activity of Atg3 by rearranging its catalytic center, while it is targeted to the membranes via Atg5 and Atg16, and promotes the transfer of Atg8 from Atg3 to the membranes.

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  • atg12 atg5 conjugate enhances e2 activity of atg3 by rearranging its catalytic site
    Nature Structural & Molecular Biology, 2013
    Co-Authors: Machiko Sakohnakatogawa, Nobuo N. Noda, Hitoshi Nakatogawa, Hiromi Kirisako, Fuyuhiko Inagaki, Kazuaki Matoba, Eri Asai, Junko Ishii, Yoshinori Ohsumi

    Abstract:

    In the yeast autophagy system, the Atg12–Atg5 conjugate acts as an E3 to promote the E2 activity of Atg3, which conjugates Atg8 to phosphatidylethanolamine. Now structural and biochemical analyses reveal that Atg12–Atg5 induces a rearrangement in the catalytic center of Atg3, which employs a threonine residue in addition to the active cysteine to catalyze the conjugation reaction.

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Nobuo N. Noda – One of the best experts on this subject based on the ideXlab platform.

  • ATG7 Activates an Autophagy-Essential Ubiquitin-like Protein Atg8 through Multi-Step Recognition.
    Journal of Molecular Biology, 2018
    Co-Authors: Masaya Yamaguchi, Yuko Fujioka, Hironori Suzuki, Yoshinori Ohsumi, Fuyuhiko Inagaki, Kenji Satoo, Nobuo N. Noda

    Abstract:

    Atg8 is a unique ubiquitin-like protein that is covalently conjugated with a phosphatidylethanolamine through reactions similar to ubiquitination and plays essential roles in autophagy. ATG7 is the E1 enzyme for Atg8, and it activates the C-terminal Gly116 of Atg8 using ATP. Here, we report the crystal structure of Atg8 bound to the C-terminal domain of ATG7 in an unprecedented mode. Atg8 neither contacts with the central β-sheet nor binds to the catalytic site of ATG7, both of which were observed in previously reported ATG7-Atg8 structures. Instead, Atg8 binds to the C-terminal α-helix and crossover loop, thereby changing the autoinhibited conformation of the crossover loop observed in the free ATG7 structure into a short helix and a disordered loop. Mutational analyses suggested that this interaction mode is important for the activation reaction. We propose that ATG7 recognizes Atg8 through multiple steps, which would be necessary to induce a conformational change in ATG7 that is optimal for the activation reaction.

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  • the intrinsically disordered protein atg13 mediates supramolecular assembly of autophagy initiation complexes
    Developmental Cell, 2016
    Co-Authors: Hayashi Yamamoto, Yuko Fujioka, Sho Suzuki, Daisuke Noshiro, Hironori Suzuki, Chika Kondokakuta, Yayoi Kimura, Hisashi Hirano, Toshio Ando, Nobuo N. Noda

    Abstract:

    Autophagosome formation in yeast entails starvation-induced assembly of the pre-autophagosomal structure (PAS), in which multiple Atg1 complexes (composed of Atg1, Atg13, and the Atg17-Atg29-Atg31 subcomplex) are initially engaged. However, the molecular mechanisms underlying the multimeric assembly of these complexes remain unclear. Using structural and biological techniques, we herein demonstrate that Atg13 has a large intrinsically disordered region (IDR) and interacts with two distinct Atg17 molecules using two binding regions in the IDR. We further reveal that these two binding regions are essential not only for Atg1 complex assembly in vitro, but also for PAS organization in vivo. These findings underscore the structural and functional significance of the IDR of Atg13 in autophagy initiation: Atg13 provides intercomplex linkages between Atg17-Atg29-Atg31 complexes, thereby leading to supramolecular self-assembly of Atg1 complexes, in turn accelerating the initial events of autophagy, including autophosphorylation of Atg1, recruitment of Atg9 vesicles, and phosphorylation of Atg9 by Atg1.

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  • architecture of the atg12 atg5 atg16 complex and its molecular role in autophagy
    Autophagy: Cancer Other Pathologies Inflammation Immunity Infection and Aging#R##N#Volume 3 – Mitophagy, 2014
    Co-Authors: Nobuo N. Noda, Fuyuhiko Inagaki

    Abstract:

    Atg5 is covalently modified with Atg12 via reactions that are similar to ubiquitination, and it noncovalently interacts with Atg16. Formation of the Atg12–Atg5–Atg16 complex is essential for its E3-like function: facilitation of Atg8 transfer from Atg3 to phosphatidylethanolamine at autophagic membranes. Structural studies on the Atg12–Atg5–Atg16 complex revealed that the unique architecture of this protein complex is totally distinct from the other E3 enzymes. The Atg12–Atg5–Atg16 complex interacts directly with Atg3 via Atg12, and enhances the conjugase activity of Atg3 by rearranging its catalytic center, while it is targeted to the membranes via Atg5 and Atg16, and promotes the transfer of Atg8 from Atg3 to the membranes.

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