It is well established that the insulin receptor phosphorylates cellular substrates which act to dock proteins with SH2 domains. However, we have recently found non-SH2 phosphotyrosine binding (KFB) domains in the insulin receptor substrates, IRS-1 and Shc. I want to know how PTB domains participate in catalysis. Do they work by increasing the local concentration of the substrate? Do they hold the substrate at the enzyme (receptor) active site to facilitate multi-site phosphorylation? Do FTB domains act as allosteric regulators as has recently been shown for SH2 domains? To address these questions I have outlined a two-pronged plan of attack. I will crystallize the PTB domain of IRS-1 and determine its three-dimensional structure. In addition, l will conduct series of biochemical experiments to show how it participates in substrate phosphorylation reactions.
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