The Hardy Lab is very interested in identifying and exploiting allosteric sites. One of the richest sources of information about allosteric sites that we have developed thus far is probing the historical record of functional sites of phosphorylation. By studying how phosphorylation impacts caspase function, we have uncovered four new mechanisms by which phosphorylationimpacts caspase function. Phosphorylation disrupts loop conformation and prevents substrate binding (caspase-6), prevents recognition by an upstream caspase (caspase-7), directly blocks substrate binding (caspase-9) and leads to unfolding of the caspase-9 core in another case. These studies not only improve our understanding of caspase biology, they also provide ideas for exploitable mechanisms for controlling caspase function.
