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Structure and Signaling functions of the Plexin and Eph Transmembrane Receptors

The primary goal of my research program is to determine how cell signaling mechanisms employ protein-protein and protein-membrane interactions in two different transmembrane receptors: The plexin and Eph receptor family. These receptors make guidance and cell positional decisions in immune, neuronal and in cardiovascular system development. Importantly, since the plexin and Eph receptors regulate cell motility, a principal aspect of our studies relates to cancer, as several oncogenic mutations are known in the receptors. Plexins also interact directly with membrane anchored Rho- and Ras GTPases; these are also key proteins involved in cancer. Protein biophysics is central to our understanding of the cell signaling mechanisms these transmembrane receptors employ. My laboratory pursues an interdisciplinary approach, applying a wide range of tools in a problem orientated manner. These tools range from classical structural biology (principally solution NMR but recently also x-ray crystallography), to extensive mutagenesis coupled with a characterization of the interaction thermodynamics and kinetics, to computational modeling/prediction of protein-protein complexes and the behavior of the complexes at the plasma membrane. Functional in vivo characterization of the receptors is carried out through collaborations at present. This multifaceted picture will explain at the molecular level the specificity and signaling mechanisms of the plexin and Eph receptor family. The basic knowledge obtained will allow us to design agents that can be used to monitor and manipulate cell signaling events, e.g. in the diseases associated with plexin and Eph receptors. In a collaboration we have already carried out in silico screening and are testing the small molecules identified in a chemical biology approach.