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PreprintCited by 50Autophagy in Disease and TherapyCellular transport and secretionAdvanced Electron Microscopy Techniques and Applications

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Structural basis for lipid transfer by the ATG2A-ATG9A complex

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Wang, Yang, Dahmane, Selma, Ti, Rujuan, Mai, Xinyi, Zhu, Lizhe, Carlson, Lars-Anders, Stjepanovic, Goran·2023·Nature Structural & Molecular Biology
DOI 10.1101/2023.07.08.548186

Preprint — published as 10.1038/s41594-024-01376-6

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Abstract

Autophagy is characterized by the formation of double-membrane vesicles called autophagosomes. ATG2A and ATG9A play an essential role in autophagy by mediating lipid transfer and re-equilibration between membranes for autophagosome formation. Here we report the cryo-EM structures of human ATG2A-WIPI4 complex at 3.2 Å, and ATG2A-WIPI4-ATG9A complex at 7 Å resolution. The ATG2A structure is characterized by a central hydrophobic cavity formed by a network of β-strands that facilitates lipid transfer, and highly flexible N- and C-terminal domains. Molecular dynamics simulations of the ATG2A N-terminal domain revealed the mechanism of lipid-extraction from the donor membranes while the ATG2A-ATG9A complex structure provides insights into the later stages of the lipid transfer reaction. ATG9A-ATG2A structural analysis revealed a 1:1 stoichiometry, directly aligning the ATG9A lateral pore with ATG2A lipid transfer cavity, hence allowing for a direct transfer of lipids from ATG2A. The ATG9A trimer can interact with both N- and C-terminal tip of rod-shaped ATG2A. Cryo-electron tomography of ATG2A-liposome binding states shows that ATG2A tethers lipid vesicles at different orientations. In summary, this study provides a molecular basis for the growth of the phagophore membrane, and lends structural insights into spatially coupled lipid transport and re-equilibration during autophagosome formation.

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Metadata

Authors
Wang, Y., Dahmane, S., Ti, R., Mai, X., Zhu, L., Carlson, L.-A., & Stjepanovic, G.
Affiliations
  • Chinese University of Hong Kong (HK)
  • Umeå Centre for Microbial Research (SE)
  • Chinese University of Hong Kong, Shenzhen (CN)
Corresponding author
  • Zhu, Lizhe
  • Carlson, Lars-Anders
ORCID
Venue
Nature Structural & Molecular Biology
Publisher
openRxiv
Published
2023-07-08
Volume
32
Issue
1
Pages
35-47
ISSN
1545-9985 (ISSN-L)
DOI
10.1101/2023.07.08.548186
OpenAlex
W4401818198
Cited by
50
References
1
Citations by year
2026: 17 · 2025: 26 · 2024: 5 · 2023: 2
FWCI
14.56
Type
journal article
Language
en
Open access
Locations
  • Nature Structural & Molecular Biology (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
Funders
  • Kempe Foundation
  • National Natural Science Foundation of China (31950410540, 31971179)
  • Knut och Alice Wallenbergs Stiftelse
  • Vetenskapsrådet (VR-RFI 2016-00968, 2016‐00968, 2021-01145, 2018-, 2018-05851)
  • Chinese University of Hong Kong
  • Kempestiftelserna (NMI VR-RFI 2016-00968)
  • Science for Life Laboratory (VR-RFI 2016-00968)
  • Center for Exercise Medicine, University of Alabama at Birmingham
  • Shenzhen Fundamental Research and Discipline Layout project (RCYX20200714114645019, JCYJ20200109150003938)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Advanced Electron Microscopy Techniques and Applications
Keywords
ATG2A, ATG9A, autophagy, lipid transfer, autophagosome formation, membrane tethering, protein complex structure
MeSH terms
Autophagosomes, Autophagy-Related Proteins, Autophagy, Humans, Liposomes, Membrane Proteins, Models, Molecular, Protein Binding, Cryoelectron Microscopy, Vesicular Transport Proteins, Molecular Dynamics Simulation

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