9bs1

Cryo-EM structure of the S. cerevisiae lipid flippase Neo1 bound with PI4P in the E2P state

spinqualitylabelsall models 9bs1, resolution 3.71Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9bs1 is a 1 chain structure with sequence from Saccharomyces cerevisiae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.71Å Ligands: A1ARJ, BEF Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function ATC7_YEAST This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the transport of phospholipids (Potential). Leads to neomycin-resistance when overexpressed. Required for traffic between late Golgi and early endosomes. Publication Abstract from PubMed Neomycin, an aminoglycoside antibiotic, has robust antibacterial properties, yet its clinical utility is curtailed by its nephrotoxicity and ototoxicity. The mechanism by which the polycationic neomycin enters specific eukaryotic cell types remains poorly understood. In budding yeast, NEO1 is required for neomycin resistance and encodes a phospholipid flippase that establishes membrane asymmetry. Here, we show that mutations altering Neo1 substrate recognition cause neomycin hypersensitivity by exposing phosphatidylinositol-4-phosphate (PI4P) in the plasma membrane extracellular leaflet. Human cells also expose extracellular PI4P upon knockdown of ATP9A, a Neo1 ortholog and ATP9A expression level correlates to neomycin sensitivity. In yeast, the extracellular PI4P is initially produced in the cytosolic leaflet of the plasma membrane and then delivered by Osh6-dependent nonvesicular transport to the endoplasmic reticulum (ER). Here, a portion of PI4P escapes degradation by the Sac1 phosphatase by entering the ER lumenal leaflet. COPII vesicles transport lumenal PI4P to the Golgi where Neo1 flips this substrate back to the cytosolic leaflet. Cryo-EM reveals that PI4P binds Neo1 within the substrate translocation pathway. Loss of Neo1 activity in the Golgi allows secretion of extracellular PI4P, which serves as a neomycin receptor and facilitates its endocytic uptake. These findings unveil novel mechanisms of aminoglycoside sensitivity and phosphoinositide homeostasis, with important implications for signaling by extracellular phosphoinositides. P4-ATPase control over phosphoinositide membrane asymmetry and neomycin resistance.,Jain BK, Duan HD, Valentine C, Samiha A, Li H, Graham TR bioRxiv [Preprint]. 2025 Mar 3:2025.03.03.641220. doi: 10.1101/2025.03.03.641220. PMID:40093091 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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