Merck Frosst award lecture 1995. La conference Merck Frosst 1995. Structural studies of lipoproteins and their apolipoprotein components.
Lipid transport processes via the circulatory system of animals are a vital function that utilizes highly specialized lipoprotein complexes. These complexes of protein and lipid impart solubility to otherwise insoluble lipids. The apoprotein components of lipoprotein complexes serve to stabilize the lipid components and modulate particle metabolism and function as ligands for receptor-mediated endocytosis of lipoproteins. We have used an insect (Manduca sexta) model system for studies of lipid transport. In this system, flight activity elicits a dramatic increase in the demand for glycerolipid fuel molecules by flight muscle tissue. These lipids are mobilized from a storage organ and transported through the hemolymph (blood) to the flight muscle by the lipoprotein, lipophorin. This system possesses the unique property that lipids are loaded onto pre-existing high density lipophorin through the action of a lipid transfer particle (LTP). LTP is a high molecular weight hemolymph component that facilitates net vectorial lipid transfer from fat body tissue to lipophorin. The increase in lipid content of the lipoprotein induces association of a low molecular weight amphipathic exchangeable apolipoprotein, apolipophorin III (apoLp-III). ApoLp-III is a 18 kDa protein that normally exists as a water-soluble monomeric hemolymph protein. The structural properties of apoLp-III have been investigated by X-ray crystallography. ApoLp-III from Locusta migratoria adopts a five helix bundle conformation wherein each of the amphipathic helices orients with its hydrophobic face directed toward the interior of the bundle. It has been hypothesized that lipid association requires a dramatic conformational change wherein the helix bundle opens about putative hinge domains located in the loops between helices. The data accumulated support the concept that apoLp-III is a member of the broad class of exchangeable apolipoproteins and structural information learned from this system is directly applicable to analogous proteins in higher organisms.
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Department of Biochemistry, University of Alberta, Edmonton, Canada.
D000818:Animals; D001053:Apolipoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001671:Biochemistry / Q000266:history; D002170:Canada; D002352:Carrier Proteins / Q000378:metabolism; D018360:Crystallography, X-Ray; D004705:Endocytosis; D004734:Energy Metabolism; D005426:Flight, Animal / Q000502:physiology; D006017:Glycolipids / Q000378:metabolism; D006110:Grasshoppers / Q000235:genetics / Q000378:metabolism; D006458:Hemolymph / Q000378:metabolism; D049673:History, 20th Century; D006801:Humans; D008024:Ligands; D008074:Lipoproteins / Q000737:chemistry* / Q000378:metabolism; D046911:Macromolecular Substances; D018402:Manduca / Q000378:metabolism; D008958:Models, Molecular; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship
D001053:Apolipoproteins; D002352:Carrier Proteins; C511922:GLTP protein, human; D006017:Glycolipids; D008024:Ligands; D008074:Lipoproteins; D046911:Macromolecular Substances; D011993:Recombinant Fusion Proteins; C042470:apolipophorin III; C030363:lipid transfer protein