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J. Biol. Chem., Vol. 283, Issue 26, 17797-17804, June 27, 2008

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Mechanisms of Ligand Transfer by the Hepatic Tocopherol Transfer Protein^*

Samantha Morley, Matt Cecchini, Wendy Zhang, Alessandro Virgulti, Noa Noy^¶, Jeffrey Atkinson, and Danny Manor^¶1

From the Cornell University, Ithaca, New York, 14853, Department of Chemistry, Brock University, St. Catharines, Ontario L2S 3A1, Canada, and ^¶Case Western Reserve University School of Medicine, Cleveland, Ohio 44106

-Tocopherol is a member of the vitamin E family that functions as the principal fat-soluble antioxidant in vertebrates. Body-wide distribution of tocopherol is regulated by the hepatic -tocopherol transfer protein (TTP), which stimulates secretion of the vitamin from hepatocytes to circulating lipoproteins. This biological activity of TTP is thought to stem from its ability to facilitate the transfer of vitamin E between membranes, but the mechanism by which the protein exerts this activity remains poorly understood. Using a fluorescence energy transfer methodology, we found that the rate of tocopherol transfer from lipid vesicles to TTP increases with increasing TTP concentration. This concentration dependence indicates that ligand transfer by TTP involves direct protein-membrane interaction. In support of this notion, equilibrium analyses employing filtration, dual polarization interferometry, and tryptophan fluorescence demonstrated the presence of a stable TTP-bilayer complex. The physical association of TTP with membranes is markedly sensitive to the presence of vitamin E in the bilayer. Some naturally occurring mutations in TTP that cause the hereditary disorder ataxia with vitamin E deficiency diminish the effect of tocopherol on the protein-membrane association, suggesting a possible mechanism for the accompanying pathology.

Received for publication, January 7, 2008 , and in revised form, May 2, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant DK067494 (to D. M.) and Training Grant T32-DK715827 (to S. M.). This work was also supported by a grant from the Natural Sciences and Engineering Research Council of Canada (to J. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Case Western Reserve University School of Medicine, WG-48, Cleveland, OH, 44106. Tel.: 216-368-6230; Fax: 216-368-6644; E-mail: dxm178{at}case.edu.

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