Abstract
Caspases, the cysteine proteases that initiate and control apoptotic cell death, are subject to allosteric regulation by a variety of modulators. Due to their role in cell death, caspases are of interest as drug targets for diseases ranging from cancer to neurodegeneration. The most significant hurdle to their therapeutic use appears to be related to the overlapping active-site specificities for small molecule inhibitors, which do not fully reflect their true in vivo specificities for protein substrates. Due to this complication, allosteric inhibition of individual caspases or particular caspase sub-functions is of great interest. Fortunately, caspases are extremely amenable to allosteric regulation, in large part due to their remarkably plastic substrate-binding grooves, which can be modulated by a number of distinct allosteric mechanisms. Our current work is to develop a global map of the allosteric networks across the family. We have discovered allosteric sites in caspase-6 and -9 that are natively regulated by zinc and elucidated the molecular mechanism of inhibition crystallographically. We have identified other allosteric sites, unique to caspase-3, -6, -7, -8 or -9 respectively, which are controlled by phosphorylation. The allosteric networks including these sites utilize distal control of the substrate-binding groove. Based on our understanding of these mechanisms of inhibition, we have engineered an allosterically handcuffed version of caspase-7 that can be unlocked by the intracellular reduction potential. Finally, using specially-designed nanoparticles we have delivered caspases and induced apoptosis in cancer cells. Together these findings move us closer to a full understanding of the allosteric networks controlling caspase function and therapeutically relevant allosteric control of caspases.
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