STRUCTURAL STUDIES OF LIPID/PROTEIN SYSTEMS

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Macromolecular structures will be obtained by x-ray crystallography and this data will be used to study structure/function relationships for biological systems containing both proteins and lipids. Several different proteins have already been crystallized and partially analyzed. The first, lipovitellin, is a lipoprotein containing -15% w/w of bound phospholipid. this ongoing project has taken on added interest with the discovery that the amino acid sequence of lipovitellin is in part related to that of apob100, a protein associated with human serum LDL. Levels of LDL correlate with a variety of cardiovascular diseases, particularly atherosclerosis. The second project involves structural studies of fatty acid binding proteins (FABPs). These small proteins are members of a larger family of structurally similar molecules responsible for either intracellular shuttling or extracellular transport of fatty acids or other water insoluble ligands. In some cells such as adipocytes, regulation of fat mobilization occurs through several different mechanisms. One appears to be under the influence of insulin and its receptor, and involves phosphorylation of adipocyte FABP. This may be the reaction which regulates lipid mobilization in fat tissue. Using x-ray analysis, the structure of recombinant liver and adipocyte FABP will be determined. In a related focussing of changing the protein conformation to a form which has some catalytic esterase activity. The third project involves single crystal x-ray studies of another recombinant protein, the precursor form of mitochondrial malate dehydrogenase, premMDH. PremMDH is the form of malate dehydrogenase which is biosynthesized in cytosol. By some unknown mechanism it is recognized by and translocated to the inner membrane matrix of mitochondria. At that point, a proteolytic reaction occurs and the mature form of malate dehydrogenase (-22 amino acids from the NH2-terminal) is formed. The important biological questions center on the structural basis for the recognition and translocation process. The latter involves passage through bilayer lipid.