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

Shintaro Maeda, Hayashi Yamamoto, Lisa N. Kinch, Christina M. Garza, Satoru Takahashi, Chinatsu Otomo, Nick V. Grishin, Stefano Forli, Noboru Mizushima, Takanori Otomo

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1194-1201
Number of pages8
JournalNature Structural and Molecular Biology
Volume27
Issue number12
DOIs
StatePublished - Dec 2020

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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