Apolipophorin II/I, Apolipoprotein B, Vitellogenin, and Microsomal Triglyceride Transfer Protein Genes Are Derived from a Common Ancestor

Abstract

Large lipid transfer proteins (LLTP) are nonexchangeable apolipoproteins and intracellular lipid-exchange proteins involved in the assembly, secretion, and metabolism of lipoproteins. We have identified contiguous conserved sequence motifs in alignments of insect apolipophorin II/I precursor (apoLp-II/I), human apolipoprotein B (apoB), invertebrate and vertebrate vitellogenins (VTG), and the large subunit of mammalian microsomal triglyceride transfer protein (MTP). Conserved motifs present in the N-terminal part of nonexchangeable apolipoproteins encompass almost completely the large subunit of MTP, suggesting a derivation from a common ancestral functional unit, termed large lipid transfer (LLT) module. Divergence of LLTP from a common ancestor is supported by (1) the statistical significance of the combined match scores obtained after motif-based database searches, (2) the presence of several identical amino acid residues in all LLTP sequences currently available, (3) the conservation of hydrophobic clusters in an alpha-helical domain, (4) the phylogenetic analysis of the conserved sequences related to the von Willebrand factor D (VWD) module identified in nonexchangeable apolipoproteins, and (5) the presence of four and one ancestral exon boundaries in the LLT and VWD modules, respectively. Our data indicate that the genes coding for apoLp-II/I, apoB, VTG, and the MTP large subunit are members of the same multigene superfamily. LLTP have emerged from an ancestral molecule designed to ensure a pivotal event in the intracellular and extracellular transfer of lipids and liposoluble substances.

A Drosophila Microsomal Triglyceride Transfer Protein Homolog Promotes the Assembly and Secretion of Human Apolipoprotein B

“…ApoLp-II/I, also known as retinoid and fatty acid binding glycoprotein, is a 3351-amino acid protein that is found in its processed form associated with insect lipophorins (47,48). Although apoLp-II/I is a member of the large lipid transfer protein gene family, which includes vitellogenin, apoB, and MTP (18), its relationship to vertebrate lipoprotein assembly has not been fully appreciated (16). In part, this is because HDLp assembly by apoLp-II/I was thought by some to be an extracellular event and also because an insect ortholog of MTP had not been identified (16,17,46).…”

“…It has become clear that apoB is part of a larger gene family that includes insect, nematode, and vertebrate vitellogenins, insect apoLp-II/I, and MTP (18,48). These proteins are collectively termed "large lipid transfer proteins" reflecting the fact that each are of relatively high molecular mass (ϳ97-500 kDa) and each engages in transport of lipids or other apolar substances (18).…”

“…These proteins are collectively termed "large lipid transfer proteins" reflecting the fact that each are of relatively high molecular mass (ϳ97-500 kDa) and each engages in transport of lipids or other apolar substances (18). Although these proteins are evolutionarily related, the type and amount of lipid each transports are quite distinct as are their sites of action and range of biological functions.…”

“…The mature lipophorin, termed low density lipophorin, is then delivered to flight muscle where its lipid is discharged and used as an energy source. Although apoLp-II/I is also a homolog of apoB (18), the fat body cell-dependent assembly of HDLp, and primitive lipoprotein assembly in general, were presumed to be MTP-independent (16,19).…”

Microsomal Triglyceride Transfer Protein Promotes the Secretion of Xenopus laevis Vitellogenin A1

“…Indeed, in recent years it has become apparent that Vtgs are members of a larger gene family termed the large lipid transfer proteins (LLTP). Members of this family include Vtg, insect apolipophorin II/I, apolipoprotein B (apoB), and the microsomal triglyceride transfer protein (MTP) (3). Although these proteins are homologous, they perform rather distinct functions, suggesting that they are paralogs rather than orthologs.…”