Lukas K. Tamm, PhD
Membrane fusion and membrane protein folding (Ras signaling)
The Tamm laboratory is studying membrane protein structures and lipid -protein interactions using structural biology and biophysical approaches.
Work in the lab is currently focused on three different problems:
- They are studying the mechanism of entry of enveloped viruses into cells using influenza hemagglutinin and HIV gp41 as model systems. They have determined the structure of the fusion domain of influenza hemagglutinin in membranes by NMR and EPR spectroscopy and are now using site-directed mutants that are defective at different stages of fusion to better understand the mechanism of viral spike glycoprotein-mediated membrane fusion. Similar work is underway with HIV. Since fusion mechanisms seem to be well conserved between different enveloped viruses, these studies may also shed light on how retroviruses deliver oncogenes into cells.
- They are pushing solution NMR spectroscopy as a new method to solve structures of membrane proteins, which are still hard to solve by x-ray crystallography. In fact they were successful a few years ago to determine in collaboration with Dr. John Bushweller the first membrane protein structure by solution NMR. They have now started to tackle the structure of an isoprenylcysteine-O-carboxyl methyltransferase (ICMT), which is part of the post-translational modification system that isoprenylates the C-terminal cysteine (CaaX motif) of ras, rho, and other small G-proteins and thus facilitates their translocation to the plasma membrane. ICMTs are important cancer drug targets. For example, methotrexate produces increased amounts of S-adenosyl-homocysteine, which in turn inhibits human ICMT.
- They are studying the mechanism of SNARE-mediated fusion using single molecule and NMR techniques. SNAREs are important regulators of intracellular membrane traffic, which is disrupted in some cancers. They are also thought to be the key players in membrane fusions that lead to exocytosis and synaptic transmission. In collaboration with Dr. David Cafiso, they are looking at the interactions of SNAREs with C2 domains of synaptotagmin in an effort to understand how they may cooperate in Ca-triggered membrane fusion.