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Document Type

Open Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Chemistry

Year Degree Awarded

2017

Month Degree Awarded

February

First Advisor

Jeanne A. Hardy

Subject Categories

Biochemistry | Structural Biology

Abstract

Caspases are the cysteine proteases that govern apoptotic cell death. The regulation of these enzymes is critical in order to restrain their death-inducing capabilities until the appropriate moment. Infidelity of caspase regulation and activation underlies a plethora of human diseases ranging from cancer to neurodegeneration. This establishes a pressing need for comprehensive studies of the apoptotic caspases in order to understand all aspects of their regulation, activation, substrate preferences, structure, and function. A detailed structural view of caspase regulation would have lasting implications for future therapeutic avenues targeting caspase function or apoptosis. This dissertation chronicles caspase regulation by phosphorylation as well as zinc. A mechanistic approach uncovering the precise means by which caspases and kinases co-regulate one another offers multiple avenues for therapeutic intervention. In addition, the influence of zinc on caspase activity at biologically relevant concentrations alters the perspective on zinc regulation of apoptosis. Lastly, this work utilizes the knowledge derived from these mechanistic studies for an application in which the cell death inducing potential of an executioner caspase is harnessed by delivering the caspase to a population of cancer cells.

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