Probing the Domain Architecture and Structural Dynamics of Caspase-6 for its Specific Regulation

Caspases are cysteine aspartate proteases that direct programmed cell death in multicellular organisms. Activation of caspases is tightly regulated to secure maintenance of cellular homeostasis. The aberrant regulation of caspases can act as molecular triggers for a range of diseases from cancer to neurodegeneration. The detailed exploration of caspase structure, dynamics, function, and regulation is crucial to better understand and precisely control their cellular functions. This body of work specifically provides a multi-level understanding of the unique structural dynamics and regulation of caspase-6, the function of which is implicated in Alzheimer’s and Huntington’s diseases. A detailed map of conformational flexibility of caspase-6 upon the five stages of proteolytic activation revealed critical regions with discrete conformations that offers a comprehensive scaffold for strategic design of therapeutics for neurodegeneration. Meanwhile, the exploration on the natural mutations in caspase-6 that have arisen from abnormally regulated tumor cells uncovered key stabilizing interaction in regulatory region that appears to be exploited across the family of caspases. In addition, the finding of ATP as a natural ligand of procaspase-6 provides another layer of regulation to the already complex caspase-6-associted signaling. Finally, the discovery of the most potent and selective inhibitor of caspase-6 to date enabled specific regulation possible by targeting a unique cysteine in the most diversified region in caspases