application) The long term goal of this work is to understand the structural and biochemical basis of directed cell movement. Many cells have the ability to move or alter their shapes in response to external signals. Such movements, which occur during development, immune response, and invasive tumor formation, are mediated by remodeling of the actin cytoskeleton. For spatially and temporally precise movements to occur, external signals must be interpreted and used to establish cell polarity. Actin polymerization must be specifically targeted to the cell's leading edge where it can provide the mechanical forward force for membrane protrusion. A class of adapter proteins, which include Enabled (Ena), vasodilator stimulated protein (VASP) and Wiscott-Aldrich Syndrome Protein (WASP), plays a central role in controlling actin polymerization. These proteins localize to potential leading edge sites via interactions with upstream signaling proteins. Subsequently they are thought to act as scaffolds to recruit downstream components of the actin polymerization machinery. Dr. Lim has chosen to focus on these adapter proteins and their interactions in order to understand how they are localized and how they act as switches to activate actin polymerization. Much of his effort will be directed towards a conserved recognition module found in these proteins, known as the Enabled VASP Homology 1 (EVH1) domain. EVH1 domains play a central role in initial targeting. The remainder of his effort will be directed at understanding how these proteins subsequently activate actin polymerization. He will use a combination of biophysical, structural, and cell biological approaches to address the following specific aims: (1) Elucidate the mechanism by which the Enabled VASP Homology 1 (EVH1) domain specifically recognizes proline-rich motifs found in receptors; (2) Determine if EVH1 domains are general dual recognition modules that can bind both phospholipids and peptides; (3) Determine the role of the EVH1 domain in targeting and polarity establishment in vivo; (4) Elucidate the structural and energetic basis of switching behavior in neuronal WASP.
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