2. Academic Validation
  3. Structure, lipid scrambling activity and role in autophagosome formation of ATG9A

Structure, lipid scrambling activity and role in autophagosome formation of ATG9A

  • Nat Struct Mol Biol. 2020 Dec;27(12):1194-1201. doi: 10.1038/s41594-020-00520-2.
Shintaro Maeda 1,  Hayashi Yamamoto 2,  Lisa N Kinch 3,  Christina M Garza 1,  Satoru Takahashi 2 4,  Chinatsu Otomo 1,  Nick V Grishin 3 5,  Stefano Forli 1,  Noboru Mizushima 2,  Takanori Otomo 6
Affiliations

Affiliations

  • 1 Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA.
  • 2 Department of Biochemistry and Molecular Biology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • 3 Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
  • 4 Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
  • 5 Department of Biophysics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
  • 6 Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA. totomo@scripps.edu.
PMID: 33106659 DOI: 10.1038/s41594-020-00520-2
Abstract

De novo formation of the double-membrane compartment autophagosome is seeded by small vesicles carrying membrane protein autophagy-related 9 (ATG9), the function of which remains unknown. Here we find that ATG9A scrambles Phospholipids of membranes in vitro. Cryo-EM structures of human ATG9A reveal a trimer with a solvated central pore, which is connected laterally to the cytosol through the cavity within each protomer. Similarities to ABC exporters suggest that ATG9A could be a transporter that uses the central pore to function. Moreover, molecular dynamics simulation suggests that the central pore opens laterally to accommodate lipid headgroups, thereby enabling lipids to flip. Mutations in the pore reduce scrambling activity and yield markedly smaller autophagosomes, indicating that lipid scrambling by ATG9A is essential for membrane expansion. We propose ATG9A acts as a membrane-embedded funnel to facilitate lipid flipping and to redistribute lipids added to the outer leaflet of ATG9 vesicles, thereby enabling growth into autophagosomes.

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