Molecular determinants of heritable vitamin E deficiency.

Morley, Samantha; Panagabko, Candace; Shineman, Diana; Mani, Bernhard; Stocker, Achim; Atkinson, Jeffrey; Manor, Danny (2004). Molecular determinants of heritable vitamin E deficiency. Biochemistry, 43(14), pp. 4143-4149. American Chemical Society 10.1021/bi0363073

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Tocopherol transfer protein (TTP) is a key regulator of vitamin E homeostasis. TTP is presumed to function by transporting the hydrophobic vitamin between cellular compartments, thus facilitating its secretion to the extracellular space. Indeed, recombinant TTP demonstrates marked ability to facilitate tocopherol transfer between lipid bilayers. We report the biochemical characterization of six missense mutations TTP(1) that are found in human AVED patients. We expressed the H101Q, A120T, R192H, R59W, E141K, and R221W TTP mutants in Escherichia coli, and purified the proteins to homogeneity. We then characterized TTP and its mutant counterparts with respect to their affinity for RRR-alpha-tocopherol and to their ability to catalyze tocopherol transfer between membranes. We observe the R59W, E141K, and R221W mutations, associated with the severe, early-onset version of AVED, are impaired in tocopherol binding and transfer activity. Surprisingly, despite the profound clinical effect of the R59W, E141K, and R221W mutations in vivo, their impact on TTP activity in vitro is quite benign (2-3-fold reduction in transfer kinetics). Furthermore, mutations associated with milder forms of the AVED disease, while causing pronounced perturbations in tocopherol homeostasis in vivo, are remarkably similar to the wild-type protein in the tocopherol transfer assays in vitro. Our data indicate that tocopherol transfer activity in vitro does not properly recapitulate the physiological functions of TTP. These findings suggest the possibility that the AVED syndrome may not arise from an inability of TTP to bind or to transfer alpha tocopherol, but rather from defects in other activities of the protein.

Item Type:

Journal Article (Review Article)


08 Faculty of Science > Department of Chemistry, Biochemistry and Pharmaceutical Sciences (DCBP)

UniBE Contributor:

Stocker, Achim


500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry




American Chemical Society




Anja Ebeling

Date Deposited:

11 Mar 2020 14:33

Last Modified:

05 Dec 2022 15:37

Publisher DOI:


PubMed ID:



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