7jlp
From Proteopedia
cryo-EM structure of human ATG9A in nanodiscs
Structural highlights
Function[ATG9A_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 PubMedDe 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. Structure, lipid scrambling activity and role in autophagosome formation of ATG9A.,Maeda S, Yamamoto H, Kinch LN, Garza CM, Takahashi S, Otomo C, Grishin NV, Forli S, Mizushima N, Otomo T Nat Struct Mol Biol. 2020 Oct 26. pii: 10.1038/s41594-020-00520-2. doi:, 10.1038/s41594-020-00520-2. PMID:33106659[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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