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 pa rticles occurs co-translationally after disulfide-dependent folding of the N-terminal domain of apoB but the mechanism is not understood. During a rec ent database search for protein sequences that contained similar amphipathi c beta strands to apoB-100, four vitellogenins, the precursor form of lipov itellin, an egg yolk lipoprotein, from chicken, frog, lamprey, and C. elega ns appeared on the list of candidate proteins. The X-ray crystal structure of lamprey lipovitellin is known to contain a "lipid pocket" lined by antip arallel amphipathic beta sheets. Here we report that the first 1000 residue s 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 lipi d-binding pocket of lamprey lipovitellin. We also show that most of the alp ha(1) domain of human apoB-100 has sequence and amphipathic motif homologie s to human microsomal triglyceride transfer protein (MTP), a protein requir ed for assembly of apoB-containing lipoproteins. Based upon these results, we suggest that an LV-like "proteolipid" intermediate containing a "lipid p ocket" is formed by the N-terminal portion of apoB alone or, more likely, a s a complex with MTP. This intermediate produces a lipid nidus required for assembly of apoB-containing lipoprotein particles; pocket expansion throug h the addition of: amphipathic beta strands from the beta(1) domain of apoB results in the formation of a progressively larger high density lipoprotei n (HDL)-like, then very low density lipoprotein (VLDL)-like, spheroidal lip oprotein particle.