P4-ATPases control phosphoinositide membrane asymmetry and neomycin resistance.

ABSTRACT: The aminoglycoside antibiotic neomycin 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. Cryogenic electron microscopy reveals PI4P binding to Neo1 within the substrate translocation pathway. PI4P enters the lumen of the endoplasmic reticulum and is flipped by Neo1 at the Golgi to prevent PI4P s

SUBMITTER: Jain BK 

PROVIDER: S-EPMC12270916 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature