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The Journal of Lipid Research, Vol. 40, 1401-1416, August 1999
Copyright © 1999 by Lipid Research, Inc.

Original Article

N-terminal domain of apolipoprotein B has structural homology to lipovitellin and microsomal triglyceride transfer protein: a "lipid pocket" model for self-assembly of apoB-containing lipoprotein particles

Correspondence to: Jere P. Segrest

The process of assembly of apolipoprotein (apo) B-containing lipoprotein particles occurs co-translationally after disulfide-dependent folding of the N-terminal domain of apoB but the mechanism is not understood. During a recent database search for protein sequences that contained similar amphipathic ß strands to apoB-100, four vitellogenins, the precursor form of lipovitellin, an egg yolk lipoprotein, from chicken, frog, lamprey, and C. elegans appeared on the list of candidate proteins. The X-ray crystal structure of lamprey lipovitellin is known to contain a "lipid pocket" lined by antiparallel amphipathic ß sheets. Here we report that the first 1000 residues of human apoB-100 (the ₁ domain plus the first 200 residues of the ß₁ domain) have sequence and amphipathic motif homologies to the lipid-binding pocket of lamprey lipovitellin. We also show that most of the ₁ domain of human apoB-100 has sequence and amphipathic motif homologies to human microsomal triglyceride transfer protein (MTP), a protein required for assembly of apoB-containing lipoproteins.

Based upon these results, we suggest that an LV-like "proteolipid" intermediate containing a "lipid pocket" is formed by the N-terminal portion of apoB alone or, more likely, as a complex with MTP. This intermediate produces a lipid nidus required for assembly of apoB-containing lipoprotein particles; pocket expansion through the addition of amphipathic ß strands from the ß₁ domain of apoB results in the formation of a progressively larger high density lipoprotein (HDL)-like, then very low density lipoprotein (VLDL)-like, spheroidal lipoprotein particle.—Segrest, J. P., M. K. Jones, and N. Dashti. N-terminal domain of apolipoprotein B has structural homology to lipovitellin and microsomal triglyceride transfer protein: a "lipid pocket" model for self-assembly of apoB-containing lipoprotein particles. J. Lipid Res. 1999. 40: 1401;–1416.

Supplementary key words: plasma apolipoproteins, LOCATE, microsomal triglyceride transfer protein (MTP), amphipathic ß sheets, amphipathic helixes, co-translational, vitellogenin, lipovitellin precursor, ₁ domain, ß₁ domain

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