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Lipid Biology Research Group at CHORI

Cell membranes constitute one of the fundamental structural and functional elements of living organisms. These complex mixtures of lipids and proteins form the outer boundary of the cell. They distinguish between the ‘inside" and the "outside", and allow the cell to communicate with its environment and maintain its integrity. The long term goal of Dr. Kuypers’s program is to understand how the molecular composition and organization of lipids is maintained in plasma membranes. The research is focused on the plasma membrane of the red cell , the structure of the red cell proteins involved in membrane lipid organization, and their interaction with each other and with their lipid environment. Dr. Ryan's focus is on the role of lipoproteins in the transport of lipids from the environment to the cell, which is central to the cell's continuous turnover of membrane phospholipids. Dr. Smith's group studies the enzyme complex fatty acid synthase (FAS), which can synthesize fatty acids to be used as building blocks in the synthesis of biomembranes. Dr. Saba's group studies sphingosine-based lipids, which are involved in signal transduction across biomembranes and allows communication between cells. Dr. Narayanaswami's objective is to determine interaction between amyloid beta peptides that are released from neuronal membranes and apolipoprotein E, ain a cholesterol-dependant manner process that leads to neurodegeneration.

Lipid Synthesis
The long-term objective of Dr. Smith’s program is to elucidate the structure, mechanism of action, and regulation of enzymes involved in fat synthesis. In animals, the seven enzymes required to convert malonyl-CoA to a long-chain fatty acid are integrated into a multifunctional polypeptide of 2500 amino acids, the fatty acid synthase (FAS). Fatty acids are incorporated in more complex lipids such as glycerol phospholipids and ceramide based phospholipids, important components of biomembranes. The deacylation and re-acylation process (Lands pathway) plays an important role in this process and is studied by Dr. Kuypers’s group. In addition to the formation of lipids, the breakdown of lipid molecules and the formation of lipid messengers are important facets of lipid biology. Thus, Dr. Saba’s group studies the synthesis and breakdown of sphingosine-1-phospate (S-1-P), an important lipid messenger molecule, and have recently identified and cloned the sphingosine phosphate lyase (SPL) genes of yeast, mouse, worm, and man. Dr. Kuypers has identified a role for secretory phospholipase A2 type IIa in acute lung injury in patients with sickle cell disease and trauma patients. Dr. Rangan studies the role of a thioesterase in mediating the intracellular effects of the HIV-1.

Lipid Transport
The amphipathic exchangeable apolipoproteins represent an important class of plasma protein with unique structural and functional properties. Key members of this protein class are known to adopt a globular helix bundle conformation in the lipid-free state. Upon interaction with lipid, helix bundle apolipoproteins are hypothesized to undergo a major conformational change whereupon hydrophobic regions of the protein are exposed and become available for direct interaction with lipid surface binding sites. Dr. Ryan’s group studies human apolipoprotein E, apolipoprotein A-I, and apolipophorin III using structure guided site-directed mutagenesis to test hypotheses related to the molecular basis of apolipoprotein function in stabilization of circulating lipoproteins, interaction with receptors, and activation of lipid metabolic enzymes and proteins. Dr. Oda examines the structure of apolipoproteinA-I (apoA-I), the primary protein component of high density lipoproteins (HDL), and how apoA-I structure may direct HDL function. Employing protein engineering and fluorescence spectroscopic tools, Dr. Narayanaswami investigates the molecular basis of interaction between apolipoprotein E isoforms and amyloid beta peptide that leads to amyloid and cerebrovascular plaque formation and neurodegeneration. The interaction is determined by a multitude of factors including the lipid-associated state of apoliprotein E and amyloid beta peptide, their conformational flexibility, apolipoprotein E isoform specificity and N-terminal and C-terminal domain interaction in apolipoprotein E. Transport of lipids across the membrane bilayer are studied by Dr. Kuypers. The phospholipids are organized in a specific and asymmetric fashion across the phospholipid bilayer. The loss of phospholipid asymmetry and the exposure of phosphatidylserine is observed early in apoptosis and has consequences for (red) cell physiology.

Lipid Signaling
Sphingosine-1-phosphate (S-1-P) is an endogenous lipid molecule which has been shown to regulate mammalian cell growth and survival and appears to have a role in cancer formation and/or progression. S-1-P is regulated primarily by two enzymes, sphingosine kinase (SK) and sphingosine phosphate lyase (SPL), studied by Dr. Saba and her group. Dr. Saba’s long-term focus is to take advantage of our understanding of the SPL protein and S-1-P mediated biology to provide novel therapeutic interventions for the treatment of cancer and thrombosis.

See also: Kuypers, Narayanaswami, Oda, Ryan, Saba and Smith Laboratories.

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