STRUCTURAL CELL BIOLOGY IN CARDIOVASCULAR DISEASE

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The objective of this program is to understand the Structural Biology of the macromolecular complexes involved in the transport of lipids into and out of cells. The aims of the project are: to define the 3-dimensional structures of cellular receptors and their ligands bound to LDL (Project 1): to study the formation of primordial nascent triglyceride-rich particles in the endoplasmic reticulum and understand how the secondary and tertiary structures of the N-terminal 41% apo-B regulates this process (Project 2); to understand the structure and conformation of apo-B, the 3- dimensional structure of LDL, the organization of apo-B on LDL, and to define the formation and 3-dimensional structure of exchangeable apolipoproteins on nascent ans plasma HDL (Project 3); to understand the binding of fatty acids to albumin, the transfer of fatty acids from albumin and movement across membranes into cells, structural and dynamic features of intracellular fatty acid binding proteins, and the effect of fatty acids on intracellular Ph (Project 4). State-of-the-art techniques of structural biology are used to study isolated or reconstituted macromolecular complexes. Low resolution structures of individual particles (and/or 2 dimensional arrays) often decorated with site specific labels are obtained by electron microscopy, in particular cryo-EM, combined with image analysis and reconstruction. Detailed structures of individual proteins or protein-lipid complexes are determined by x-ray crystallography. The solution structure of peptides that model regions of proteins or small proteins such as the intracellular fatty acid binding proteins are determined by multi-dimensional NMR. High resolution molecular arrangements can be superimposed onto the low resolution structure of macromolecular assemblies obtained by electron microscopy to generate a "higher resolution" macromolecular structure. These studies can provide the biological structures involved in the processes by which lipids are moved into, within, and out of cells. Such information will allow the development of new molecular based strategies to control hyper beta lipoproteinemia, fatty acid-induced cellular damage in ischemia, and arteriosclerosis.