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 i nsoluble lipids. The apoprotein components of lipoprotein complexes se rve to stabilize the lipid components and modulate particle metabolism and function as ligands for receptor-mediated endocytosis of lipoprot eins. 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 musc le tissue. These lipids are mobilized from a storage organ and transpo rted through the hemolymph (blood) to the flight muscle by the lipopro tein, lipophorin. This system possesses the unique property that lipid s are loaded onto pre-existing high density lipophorin through the act ion of a lipid transfer particle (LTP). LTP is a high molecular weight hemolymph component that facilitates net vectorial lipid transfer fro m 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 in vestigated by X-ray crystallography. ApoLp-III from Locusta migratoria adopts a five helix bundle conformation wherein each of the amphipath ic helices orients with its hydrophobic face directed toward the inter ior of the bundle. It has been hypothesized that lipid association req uires 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 th e broad class of exchangeable apolipoproteins and structural informati on learned from this system is directly applicable to analogous protei ns in higher organisms.