title: Impaired α-TTP-PIPs interaction underlies familial vitamin E deficiency.
abstract: α-Tocopherol (vitamin E) transfer protein (α-TTP) regulates the secretion of α-tocopherol from liver cells. Missense mutations of some arginine residues at the surface of α-TTP cause severe vitamin E deficiency in humans, but the role of these residues is unclear. Here, we found that wild-type α-TTP bound phosphatidylinositol phosphates (PIPs), whereas the arginine mutants did not. In addition, PIPs in the target membrane promoted the intermembrane transfer of α-tocopherol by α-TTP. The crystal structure of the α-TTP-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 α-tocopherol-binding pocket to open. Thus, PIPs have a role in promoting the release of a ligand from a lipid-transfer protein.
authors.affiliation: Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Nozomu
authors.initials: N
authors.lastname: Kono
authors.forename: Umeharu
authors.initials: U
authors.lastname: Ohto
authors.forename: Tatsufumi
authors.initials: T
authors.lastname: Hiramatsu
authors.forename: Michiko
authors.initials: M
authors.lastname: Urabe
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Uchida
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Satow
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
mesh_terms: D019943:Amino Acid Substitution; D001120:Arginine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D009154:Mutation; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D017433:Protein Structure, Secondary; D014811:Vitamin E Deficiency / Q000378:metabolism*; D024502:alpha-Tocopherol / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; C017763:alpha-tocopherol transfer protein; D001120:Arginine; D024502:alpha-Tocopherol