SMOCs: Novel Signal Transduction Complexes as New Targets for Drug Discovery

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 DESCRIPTION (provided by applicant): Formation of location-specific, higher-order signaling complexes, now called supramolecular organizing centers (SMOCs), is an almost universal feature of innate immune signaling. SMOC-mediated signal transduction is distinct from classical signal transduction, in which a chain reaction of ligand-induced conformational changes, enzyme activation and second messenger production leads to signal transmission and amplification. SMOCs illustrate important principles involving cooperativity, signal amplification, threshold behavior and time delay of response, as well as proximity-driven allosteric enzyme activation, spatial and temporal control of activation and termination, and reduction of biological noise. These key signaling concepts are at the forefront of modern signal transduction theory, and understanding them at a rigorous molecular, structural and cell biological level would transform how we approach innate immunity, at both basic and applied levels. In this Pioneer Application, we will investigate a subset of these concepts that directly guide the development of attractive new models for targeted drug discovery, using fresh ideas and methodologies. Innate immunity is critically important for host-defense and inflammation, and its dysregulation underlies many human diseases, including genetic disorders, gout, psoriasis, lupus, multiple sclerosis, neurodegenerative diseases, diabetes, ulcerative colitis and Crohn's disease, just to name a few. We propose that SMOCs provide a previously untapped druggable proteome as they offer opportunities for dominant negative, rather than competitive inhibition as a result of the cooperativity in their assembly. These target sites may include polymerization interfaces on the oligomerization domains, SMOC-induced, intrinsically weak interactions required for allosteric enzyme activation, and potential SMOC-cytoskeleton interactions required for SMOC formation in cells. The principles learned from these stud