Apolipophorin II/I, apolipoprotein B, vitellogenin, and microsomal triglyceride transfer protein genes are derived from a common ancestor

Large lipid transfer proteins (LLTP) are nonexchangeable apolipoproteins an d intracellular lipid-exchange proteins involved in the assembly, secretion , and metabolism of lipoproteins. We have identified contiguous conserved s equence motifs in alignments of insect apolipophorin II/I precursor (apoLp- II/I), human apolipoprotein B (apoB), invertebrate and vertebrate vitelloge nins (VTG), and the large subunit of mammalian microsomal triglyceride tran sfer protein (MTP). Conserved motifs present in the N-terminal part of none xchangeable apolipoproteins encompass almost completely the large subunit o f MTP, suggesting a derivation from a common ancestral functional unit, ter med large Lipid transfer (LLT) module. Divergence of LLTP from a common anc estor is supported by (1) the statistical significance of the combined matc h scores obtained after motif-based database searches, (2) the presence of several identical amino acid residues in all LLTP sequences currently avail able, (3) the conservation of hydrophobic clusters in an or-helical domain, (4) the phylogenetic analysis of the conserved sequences related to the vo n Willebrand factor D (VWD) module identified in nonexchangeable apolipopro teins, and (5) the presence of four and one ancestral exon boundaries in th e LLT and VWD modules, respectively. Our data indicate that the genes codin g for apoLp-II/I, apoB, VTG, and the MTP large subunit, are members of the same multigene super-family. LLTP have emerged from an ancestral molecule d esigned to ensure a pivotal event in the intracellular and extracellular tr ansfer of lipids and liposoluble substances.