The overall goal of this project is to understand the molecular basis by which eukaryotic signal transduction networks are assembled. Interactions between most cytoplasmic signaling proteins are mediated by modular protein-protein recognition domains. We are focusing on several such domain families including SH3, PDZ, and L27 domains, because they play a central role organizing and """"""""wiring"""""""" individual proteins into pathways. In studying these domains, our general aims are: first, to understand their biophysical mechanisms of sequence-specific recognition; second, to exploit these mechanisms to develop novel strategies for inhibitor design; and third, to understand how these domains are used to assemble higher order signaling networks.
Our specific aims are to: 1) Continue developing a novel class peptoid inhibitors of SH3 and WW domains and to test these for effects in vivo 2) Determine the general rules of PDZ domain recognition by evaluating the energetic contribution of electrostatic, hydrogen bonding, and packing interactions. 3) Characterize the structure and mechanism of L27 domains, a novel family of hetero-oligomerization modulates involved in signaling complex assembly and targeting 4) Define the degree of signaling specificity encoded by individual SH3 domains in vivo, across the entire yeast proteome.
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