ArticlebioRxiv : the preprint server for biology2026
Revealing interactions between glutathione peroxidase 4 and phosphoinositides.
Article in bioRxiv : the preprint server for biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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6 authors.
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Abstract
Glutathione peroxidase 4 (GPx4) is the primary enzyme reducing lipid hydroperoxides, preventing membrane oxidative damage and protecting against ferroptosis. GPx4 is known to engage with lipid headgroups through electrostatic interactions, positioning the substrate for reduction. This work reveals and characterizes binding of highly anionic phosphoinositides (PIP lipids) by GPx4. PIPs are vital lipids in human cells and are central to many signaling processes, particularly in cytosolic facing membranes. Lipid overlay assays confirm interactions between GPx4 and phosphorylated PIPs, comparable to known anionic lipid binders. Protein NMR describes the interaction between GPx4 and PIPs within micelles. The greatest resonance shifting occurs with trisphosphorylated PIP, suggesting that higher anionic charge leads to greater binding, a known driver of GPx4 substrate recognition. Preferred anionic interactions were also confirmed with titration and crystallographic structure analysis of inositol phosphate 4 (IP
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