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Lipoprotein biogenesis and evolution of lipid transport: an insect perspective

By Martinus Maria Wilhelmus Smolenaars


Lipids are essential to organisms as they constitute membranes, and function as energy source and reserve. In animals, lipid transport in the circulation is accomplished by lipoproteins. These macromolecular particles, consisting of one or more proteins and up to hundreds of lipid molecules, have been identified throughout the animal kingdom, but have been studied particularly in mammals and insects. Previous investigations revealed important similarities and differences between insect and mammalian lipoprotein systems, that may result from modification of the structural components involved. From this perspective, this thesis presents work on the biosynthesis of insect lipoprotein, the evolutionary origin and diversification of lipoprotein precursor proteins among animals, and sequence properties of lipoprotein receptors. \ud The two structural proteins in insect lipoprotein, apoLp-I and apoLp-II, derive from cleavage of a common precursor protein, apoLp-II/I, that is homologous to the single structural protein of mammalian lipoproteins, apoB. The involvement of an insect furin in apoLp-II/I cleavage was demonstrated using fat body tissue from the migratory locust (Locusta migratoria) and a novel recombinant insect expression system for truncated L. migratoria apoLp-II/I. Surprisingly, however, cleavage is not essential to the lipidation and secretion of lipophorin, as uncleaved apoLp-II/I was also secreted as a lipoprotein. \ud The mechanism that allows lipidation of apoLp-II/I or its two cleavage products into a lipoprotein is unknown. Sequence analysis predicts apoLp-II/I to contain clusters of amphipathic α-helices and β-strands, organized along the protein as N-α1-β-α2-C. Expression of truncation variants of L. migratoriai apoLp-II/I in a recombinant lipoprotein expression system revealed that the β cluster enables the binding of sufficient lipids to constitute a buoyant lipoprotein. A Drosophila melanogaster MTP homolog stimulated recombinant apoLp-II/I secretion as well as lipidation. These results indicate that lipoprotein assembly of insects, similar to that of mammals, depends on amphipathic clusters as well as MTP. \ud The involvement of similar elements in the biogenesis of insect and mammalian lipoproteins implies a common metazoan, and therefore ancient, origin for lipoproteins and their mechanisms for biogenesis. To gain understanding of their evolution, sequence databases were searched to categorize large lipid transfer proteins (LLTP) across the animal kingdom. This resulted in the recognition of two novel LLTP in insects in addition to vitellogenin, apoLp-II/I, and MTP. Phylogenetic analysis on conserved sequences in the LLT module revealed three subfamilies of LLTP, and the relatively close relationship of insect apoLp-II/I and mammalian apoB. \ud Animals rely on homologous members of the LDL receptor family for the cellular uptake of specific LLTP. Classification based on the non-recurring domains of LDLR family members recognizes insect lipophorin receptors, LpR, as a distinct subgroup of the LDLR family, unlike previous classification based on the number of cysteine-rich repeats in the ligand-binding domain. The distinct sequence motifs observed in the non-recurring domains of LpR may explain functional differences with mammalian LDLR family members

Topics: Biologie, lipoprotein, evolution, Locusta, lipid, cleavage, diacylglycerol, apoB, apolipoprotein, receptor
Publisher: Utrecht University
Year: 2006
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