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.
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 beta 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 beta sheets. Here we report that the first 1000 residues of human apoB-100 (the alpha(1) domain plus the first 200 residues of the beta(1) domain) have sequence and amphipathic motif homologies to the lipid-binding pocket of lamprey lipovitellin. We also show that most of the alpha(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 beta strands from the beta(1) 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
JP
Departments of Medicine and Biochemistry and the Atherosclerosis Research Unit, University of Alabama Medical Center, Birmingham, AL 35294-0012, USA.
Jones
M K
MK
Dashti
N
N
D000818:Animals; D001055:Apolipoproteins B / Q000737:chemistry* / Q000378:metabolism*; D002352:Carrier Proteins / Q000737:chemistry*; D003198:Computer Simulation; D004527:Egg Proteins / Q000737:chemistry*; D015387:Egg Proteins, Dietary; D006801:Humans; D008074:Lipoproteins / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D015203:Reproducibility of Results; D016415:Sequence Alignment / Q000379:methods; D013045:Species Specificity
D001055:Apolipoproteins B; D002352:Carrier Proteins; D004527:Egg Proteins; D015387:Egg Proteins, Dietary; D008074:Lipoproteins; C106092:microsomal triglyceride transfer protein; C001549:lipovitellin