The structure of vitellogenin provides a molecular model for the assembly and secretion of atherogenic lipoproteins

Christopher J. Mann, Timothy A. Anderson, Jacqueline Read, S. Ann Chester, Georgina B. Harrison, Silvano Köchl, Penelope J. Ritchie, Paul Bradbury, Farhana S. Hussain, Joanna Amey, Berlinda Vanloo, Maryvonne Rosseneu, Recaredo Infante, John M. Hancock, David G Levitt, Leonard J. Banaszak, James Scott, Carol C. Shoulders

Research output: Contribution to journalArticlepeer-review

166 Scopus citations

Abstract

The assembly of atherogenic lipoproteins requires the formation in the endoplasmic reticulum of a complex between apolipoprotein (apo)B, a microsomal triglyceride transfer protein (MTP) and protein disulphide isomerase (PDI). Here we show by molecular modelling and mutagenesis that the globular amino-terminal regions of apoB and MTP are closely related in structure to the ancient egg yolk storage protein, vitellogenin (VTG). In the MTP complex, conserved structural motifs that form the reciprocal homodimerization interfaces in VTG are re-utilized by MTP to form a stable heterodimer with PDI, which anchors MTP at the site of apoB translocation, and to associate with apoB and initiate lipid transfer. The structural and functional evolution of the VTGs provides a unifying scheme for the invertebrate origins of the major vertebrate lipid transport system.

Original languageEnglish (US)
Pages (from-to)391-408
Number of pages18
JournalJournal of Molecular Biology
Volume285
Issue number1
DOIs
StatePublished - Jan 8 1999

Bibliographical note

Funding Information:
We gratefully acknowledge the financial support from the British Medical Research Council and the British Heart Foundation (Grant numbers PG/95186, PG/96101 and PG/97011). J.S. also gratefully thanks the Bristol-Myers Squibb Corporation for a cardiovascular research award. We thank Professor Robert Brasseur, Drs Naveenan Navaratnam and Andrew F. Dean for helpful discussion, Teresa Narcisi, Tamsin Grantham and Dianne Sullivan for assistance at the early stages of the project, and Mrs Glennis McDonald for help in preparing the manuscript. We are also grateful to Professor Dimitris Cournaros and Drs Isabel Beucler, Veronique Clavey and Daniel Pinsembert for clinical assistance. Modelling activities were supported by a US-NIH grant (GH 13925) and the Minnesota Supercomputer Institute (University of Minnesota).

Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.

Keywords

  • Apolipoprotein B
  • Microsomal triglyceride transfer protein
  • Vitellogenin

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