Impaired α-TTP-PIPs Interaction Underlies Familial Vitamin E Deficiency

Science  31 May 2013:
Vol. 340, Issue 6136, pp. 1106-1110
DOI: 10.1126/science.1233508

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Vitamin E Out

Familial vitamin E deficiency is caused by mutations in the α-tocopherol transfer protein (α-TTP) gene. Kono et al. (p. 1106, published online 18 April; see the Perspective by Mesmin and Antonny) studied natural mutations in α-TTP. α-TTP bound phosphatidylinositol polyphosphates (PIPs), especially PI(4,5)P2, and a disease-related missense mutation abolished PIP binding but not α-tocopherol binding. The x-ray crystal structure of the α-TTP–PIP complex suggested that PIP binding opens the lid of the α-tocopherol–binding pocket to facilitate the release of α-tocopherol. Thus, PIP binding to α-TTP at the target membrane may facilitate the release of α-tocopherol in the hydrophobic pocket of α-TTP to the lipid bilayer of the target membrane, providing a mechanism for the transfer of lipids from the lipid-transfer protein to the target membrane.


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.

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