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Lukas
K.
Tamm
Degree(s): Ph.D. Graduate School: University of Basel, Switzerland Primary Appointment: Professor of Molecular Physiology and Biological Physics Research Interests: Biomembrane Structure and Function; Membrane Fusion in Viral Cell Entry and Exocytosis; Lipid-Protein Interactions Email Address: lkt2e@virginia.edu |
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Biomedical Sciences Graduate Program(s) Research Description Membrane Protein Structure, Stability and Folding Our laboratory is developing new techniques to determine the structures of integral membrane proteins. We are pushing the envelope of what is currently possible for the structure determination of membrane proteins by NMR spectroscopy. To this end, we are working to increase expression levels of membrane proteins and we are developing protocols to refold membrane proteins in lipid and detergent environments. Several proteins - some of which with therapeutic interest - are targeted in these studies. Our model protein for methods development has been the outer membrane protein A (OmpA) from E.coli. We solved its structure by NMR spectroscopy in 2001 and elucidated the mechanism of ion conduction of this ion channel. More recently (in 2007) we solved the structure of OmpG, which is currently the largest structure (33 kDa) of any integral membrane protein solved by NMR. OmpA has also been extensively used in our laboratory as a model to study the mechanism of folding and the thermodynamic stability of integral membrane proteins. These methods may now be applied to G-protein-coupled receptors or other integral membrane proteins that have been identified as potential drug targets. Key Techniques: Gating of OmpA Ion Channel Membrane Fusion in Viral Infection Although the structures of the soluble domains of many viral fusion proteins have been solved, the mechanism of membrane fusion is still poorly understood. We are studying the structures and interactions of viral fusion proteins in lipid bilayers. Most studies have been carried out with influenza hemagglutinin (HA), but similar studies with HIV gp41/gp120 and Ebola GP2 are also in progress. We have worked out a detailed 'spring-loaded boomerang' model of how influenza HA interacts with viral and cellular membranes. We have determined the structures of the influenza fusion domain in lipid bilayers by NMR and spin-label EPR spectroscopy at resting and fusion pH. We are also developing structure-function relationships for fusion by combining site-directed mutagenesis with structural and functional studies. This research opens exciting new possibilities to develop new classes of viral entry inhibitors. Key Techniques:
Structures and probable sites of action of proteins involved in intracellular vesicle membrane fusion
Supported Lipid Bilayer Technology To address some of the biological questions stated above, we have a long-standing interest in the development of supported lipid bilayers as models of biological membranes. We recently developed methods to prepare single planar lipid bilayers on soft polymer cushions on microscope slides or oxidized silicon chips. Several integral membrane proteins have been shown to be laterally mobile in these model membranes. Their motions and interactions can be studied by single-molecule total internal reflection fluorescence microscopy (TIRFM), by fluorescence recovery after photobleaching (FRAP), and by fluorescence interference contrast (FLIC) microscopy. The dynamics and assembly of lateral membrane domains ('lipid rafts') are being studied by these methods.
Design of a Tethered Polymer-Supported Lipid Bilayer
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