Structural and Cell Biology in Cardiovascular Disease

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DESCRIPTION (provided by applicant): The overall theme of this interdisciplinary Program Project is to understand the structural biology and hence structure-function relationships of the macromolecules and macromolecular complexes involved in the transport of lipids into and out of cells and between different organs of the body. The biosynthesis, assembly and disassembly, inter-conversions, receptor interactions, cofactor and enzyme substrate functions, and cellular uptake of lipids and specific proteins (apolipoproteins and other lipid-binding proteins) play key roles in the overall regulation of lipid metabolism. Biochemical defects in lipid and lipoprotein metabolism express themselves at different levels of these processes. These defects lead to alterations in the composition, structure and physical properties of the plasma lipoproteins, cellular and organelle membranes, and intracellular lipid stores that in turn may contribute to diseases such as atherosclerosis, thrombosis, myocardial ischemia, and diabetes. The overall objectives of the Progam include studies of the biogenesis, conformation, three-dimensional structure, stability, and interconversion of lipoproteins, their constituent apolipoproteins, and lipoprotein receptors together with other intra- and extra-cellular lipid binding proteins. To achieve these overall objectives, studies in the four highly inter-related projects will encompass: (a) The effects of protein and lipid composition and environmental conditions on the stability of model discoidal HDL, the structural and kinetic determinants of protein-lipid interactions in lipid-free and lipid-poor apolipoproteins, and the key molecular determinants of LDL stability. (Project 1), (b) Critical domains in the N terminal of apoB necessary to initiate specific lipid-binding, assembly and secretion, the interfacial chemistry of these domains and synthetic consensus sequences of apoB, and the structure of the N terminal domains of normal and mutant apoB. (Project 2), (c) The conformation and structure of exchangeable apolipoproteins and the conformational changes on lipid binding and as discoidal nascent HDL is converted to spherical HDL, the three-dimensional structure of LDL and apo-B on LDL, the structure of the ligand binding domain of the LDL receptor, and the structure of LDL with bound receptor. (Project 3), and (d)The molecular interactions of fatty acids with fatty acid binding proteins, the structures and dynamics of cytosolic fatty acid binding proteins and interactions with ligands, and the transport of fatty acids in model membranes and cells (Project 4). An interdisciplinary approach that encompasses protein and lipid biochemistry and biophysics, molecular and cell biology, and state-of-the-art methods of computational and structural biology is used to obtain these objectives. Such information will allow the development of new molecular-based strategies to control dyslipoproteinemias, fatty acid-induced cellular damage in ischemia, diabetes and arteriosclerosis.