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.
Kuyperss 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.
The long-term objective of Dr. Smiths 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. Kuyperss 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. Sabas 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.
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. Ryans 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.
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. Sabas 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