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 G Levitt, Maryvonne Rosseneu, James Scott, Carol C. Shoulders

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)30372-30377
Number of pages6
JournalJournal of Biological Chemistry
Volume275
Issue number39
DOIs
StatePublished - Sep 29 2000

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    Read, J., Anderson, T. A., Ritchie, P. J., Vanloo, B., Amey, J., Levitt, D. G., Rosseneu, M., Scott, J., & Shoulders, C. C. (2000). A mechanism of membrane neutral lipid acquisition by the microsomal triglyceride transfer protein. Journal of Biological Chemistry, 275(39), 30372-30377. https://doi.org/10.1074/jbc.C000364200