8Y1L

Cryo-EM structure of human N-terminally bound ATG9A-ATG2A-WIPI4 complex

Summary for 8Y1L

• Entry DOI: 10.2210/pdb8y1l/pdb
• EMDB information: 38839
• Descriptor: Autophagy-related protein 9A, WD repeat domain phosphoinositide-interacting protein 4, Autophagy-related protein 2 homolog A (3 entities in total)
• Functional Keywords: lipid transfer, atg9a-atg2a-wipi4 complex, single particle cryo-em, autophagy, lipid transport/membrane protein, lipid transport-membrane protein complex, lipid transport
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 536669.91

Authors

Wang, Y.,Stjepanovic, G. (deposition date: 2024-01-25, release date: 2024-09-04)

Primary citation

Wang, Y.,Dahmane, S.,Ti, R.,Mai, X.,Zhu, L.,Carlson, L.A.,Stjepanovic, G.
Structural basis for lipid transfer by the ATG2A-ATG9A complex.
Nat.Struct.Mol.Biol., 2024

PubMed Abstract: Autophagy is characterized by the formation of double-membrane vesicles called autophagosomes. Autophagy-related proteins (ATGs) 2A and 9A have an essential role in autophagy by mediating lipid transfer and re-equilibration between membranes for autophagosome formation. Here we report the cryo-electron microscopy structures of human ATG2A in complex with WD-repeat protein interacting with phosphoinositides 4 (WIPI4) at 3.2 Å and the ATG2A-WIPI4-ATG9A complex at 7 Å global resolution. On the basis of molecular dynamics simulations, we propose a mechanism of lipid extraction from the donor membranes. Our analysis revealed 3:1 stoichiometry of the ATG9A-ATG2A complex, directly aligning the ATG9A lateral pore with ATG2A lipid transfer cavity, and an interaction of the ATG9A trimer with both the N-terminal and the C-terminal tip of rod-shaped ATG2A. Cryo-electron tomography of ATG2A liposome-binding states showed 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.

PubMed: 39174844
DOI: 10.1038/s41594-024-01376-6

Experimental method

ELECTRON MICROSCOPY (7.05 Å)