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Multifaceted membrane interactions of human Atg3 promote LC3-phosphatidylethanolamine conjugation during autophagy

Author

Listed:
  • Yansheng Ye

    (Pennsylvania State University College of Medicine)

  • Erin R. Tyndall

    (Pennsylvania State University College of Medicine)

  • Van Bui

    (Pennsylvania State University College of Medicine)

  • Maria C. Bewley

    (Pennsylvania State University College of Medicine)

  • Guifang Wang

    (Pennsylvania State University College of Medicine)

  • Xupeng Hong

    (Pennsylvania State University College of Medicine)

  • Yang Shen

    (US National Institutes of Health)

  • John M. Flanagan

    (Pennsylvania State University College of Medicine)

  • Hong-Gang Wang

    (Pennsylvania State University College of Medicine)

  • Fang Tian

    (Pennsylvania State University College of Medicine)

Abstract

Autophagosome formation, a crucial step in macroautophagy (autophagy), requires the covalent conjugation of LC3 proteins to the amino headgroup of phosphatidylethanolamine (PE) lipids. Atg3, an E2-like enzyme, catalyzes the transfer of LC3 from LC3-Atg3 to PEs in targeted membranes. Here we show that the catalytically important C-terminal regions of human Atg3 (hAtg3) are conformationally dynamic and directly interact with the membrane, in collaboration with its N-terminal membrane curvature-sensitive helix. The functional relevance of these interactions was confirmed by in vitro conjugation and in vivo cellular assays. Therefore, highly curved phagophoric rims not only serve as a geometric cue for hAtg3 recruitment, but also their interaction with hAtg3 promotes LC3-PE conjugation by targeting its catalytic center to the membrane surface and bringing substrates into proximity. Our studies advance the notion that autophagosome biogenesis is directly guided by the spatial interactions of Atg3 with highly curved phagophoric rims.

Suggested Citation

  • Yansheng Ye & Erin R. Tyndall & Van Bui & Maria C. Bewley & Guifang Wang & Xupeng Hong & Yang Shen & John M. Flanagan & Hong-Gang Wang & Fang Tian, 2023. "Multifaceted membrane interactions of human Atg3 promote LC3-phosphatidylethanolamine conjugation during autophagy," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41243-4
    DOI: 10.1038/s41467-023-41243-4
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    References listed on IDEAS

    as
    1. Yansheng Ye & Erin R. Tyndall & Van Bui & Zhenyuan Tang & Yan Shen & Xuejun Jiang & John M. Flanagan & Hong-Gang Wang & Fang Tian, 2021. "An N-terminal conserved region in human Atg3 couples membrane curvature sensitivity to conjugase activity during autophagy," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    2. Yumei Zheng & Yu Qiu & Christy R. R. Grace & Xu Liu & Daniel J. Klionsky & Brenda A. Schulman, 2019. "A switch element in the autophagy E2 Atg3 mediates allosteric regulation across the lipidation cascade," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
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