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J. Biol. Chem., Vol. 275, Issue 39, 30372-30377, September 29, 2000

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A Mechanism of Membrane Neutral Lipid Acquisition by the Microsomal Triglyceride Transfer Protein^*

Jacqueline Read, Timothy A. Anderson^§, Penelope J. Ritchie, Berlinda Vanloo^¶, Joanna Amey, David Levitt^§, Maryvonne Rosseneu^¶, James Scott, and Carol C. Shoulders^**

From the  Molecular Medicine Group, MRC Clinical Sciences Centre, and  National Heart and Lung Institute, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London W12 ONN, United Kingdom, the ^§ Department of Biochemistry, University of Minnesota Medical School, Minneapolis, Minnesota 55455-0326, and the ^¶ Department of Biochemistry, Laboratorium voor Lipoproteine Chemie, University of Gent, Hospitaalstraat 13, 8-9000 Gent, Belgium

The microsomal triglyceride transfer protein (MTP) and apolipoprotein B (apoB) belong to the vitellogenin (VTG) family of lipid transfer proteins. MTP is essential for the intracellular assembly and secretion of apoB-containing lipoproteins, the key intravascular lipid transport proteins in vertebrates. We report the predicted three-dimensional structure of the C-terminal lipid binding cavity of MTP, modeled on the crystal structure of the lamprey VTG gene product, lipovitellin. The cavity in MTP resembles those found in the intracellular lipid-binding proteins and bactericidal/permeability-increasing protein. Two conserved helices, designated A and B, at the entrance to the MTP cavity mediate lipid acquisition and binding. Helix A (amino acids 725-736) interacts with membranes in a manner similar to viral fusion peptides. Mutation of helix A blocks the interaction of MTP with phospholipid vesicles containing triglyceride and impairs triglyceride binding. Mutations of helix B (amino acids 781-786) and of N780Y, which causes abetalipoproteinemia, have no impact on the interaction of MTP with phospholipid vesicles but impair triglyceride binding. We propose that insertion of helix A into lipid membranes is necessary for the acquisition of neutral lipids and that helix B is required for their transfer to the lipid binding cavity of MTP.

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