8KBZ

Cryo-EM structure of human ATG9A in LMNG micelles

Summary for 8KBZ

• Entry DOI: 10.2210/pdb8kbz/pdb
• EMDB information: 37088
• Descriptor: Autophagy-related protein 9A (1 entity in total)
• Functional Keywords: lipid scramblase, atg9a, single particle cryo-em, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 3
• Total formula weight: 283653.09

Authors

Yang, W.,Goran, S. (deposition date: 2023-08-04, release date: 2024-08-07, Last modification date: 2025-01-29)

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., 32:35-47, 2025

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 (3.97 Å)