The molecular basis of vitamin E retention: structure of human alpha-tocopherol transfer protein.
Alpha-tocopherol transfer protein (alpha-TTP) is a liver protein responsible for the selective retention of alpha-tocopherol from dietary vitamin E, which is a mixture of alpha, beta, gamma, and delta-tocopherols and the corresponding tocotrienols. The alpha-TTP-mediated transfer of alpha-tocopherol into nascent VLDL is the major determinant of plasma alpha-tocopherol levels in humans. Mutations in the alpha-TTP gene have been detected in patients suffering from low plasma alpha-tocopherol and ataxia with isolated vitamin E deficiency (AVED). The crystal structure of alpha-TTP reveals two conformations. In its closed tocopherol-charged form, a mobile helical surface segment seals the hydrophobic binding pocket. In the presence of detergents, an open conformation is observed, which probably represents the membrane-bound form. The selectivity of alpha-TTP for RRR-alpha-tocopherol is explained from the van der Waals contacts occurring in the lipid-binding pocket. Mapping the known mutations leading to AVED onto the crystal structure shows that no mutations occur directly in the binding pocket.
Meier
Reto
R
Department of Chemistry and Biochemistry, University of Berne, Freiestrasse 3, 3012 Berne, Switzerland.
Tomizaki
Takashi
T
Schulze-Briese
Clemens
C
Baumann
Ulrich
U
Stocker
Achim
A
D001259:Ataxia / Q000150:complications / Q000235:genetics; D001665:Binding Sites; D001692:Biological Transport; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D008024:Ligands; D050356:Lipid Metabolism; D008958:Models, Molecular; D011487:Protein Conformation; D012174:Retinitis Pigmentosa / Q000150:complications / Q000235:genetics; D013379:Substrate Specificity; D014810:Vitamin E / Q000378:metabolism*; D014811:Vitamin E Deficiency / Q000150:complications / Q000235:genetics; D024502:alpha-Tocopherol / Q000031:analogs & derivatives / Q000378:metabolism
D002352:Carrier Proteins; D008024:Ligands; C017763:alpha-tocopherol transfer protein; D014810:Vitamin E; D024502:alpha-Tocopherol