8y1l
From Proteopedia
Cryo-EM structure of human N-terminally bound ATG9A-ATG2A-WIPI4 complex
Structural highlights
FunctionATG9A_HUMAN Involved in autophagy and cytoplasm to vacuole transport (Cvt) vesicle formation. Plays a key role in the organization of the preautophagosomal structure/phagophore assembly site (PAS), the nucleating site for formation of the sequestering vesicle. Cycles between a juxta-nuclear trans-Golgi network compartment and late endosomes. Nutrient starvation induces accumulation on autophagosomes. Starvation-dependent trafficking requires ULK1, ATG13 and SUPT20H.[1] Publication Abstract from PubMedAutophagy 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 A and the ATG2A-WIPI4-ATG9A complex at 7 A 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. Structural basis for lipid transfer by the ATG2A-ATG9A complex.,Wang Y, Dahmane S, Ti R, Mai X, Zhu L, Carlson LA, Stjepanovic G Nat Struct Mol Biol. 2024 Aug 22. doi: 10.1038/s41594-024-01376-6. PMID:39174844[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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