alpha-Tocopherol (vitamin E) transfer protein (alpha-7P) regulates the secretion of a-tocopherol from liver cells. Missense mutations of some arginine residues at the surface of alpha-TIP cause severe vitamin E deficiency in humans, but the role of these residues is unclear. Here, we found that wild-type a-UP bound phosphatidylinositol phosphates (PIPs), whereas the arginine mutants did not. In addition, PIPs in the target membrane promoted the intermembrane transfer of alpha-tocopherot by alpha-UP. The crystal structure of the alpha-UP PIPs complex revealed that the disease-related arginine residues interacted with phosphate groups of the PIPs and that the PIPs binding caused the lid of the alpha-tocopherol binding pocket to open. Thus, PIPs have a rote in promoting the release of a ligand from a lipid-transfer protein.