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Document Type

Open Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Chemistry

Year Degree Awarded

2018

Month Degree Awarded

February

First Advisor

Jeanne A. Hardy

Second Advisor

Scott C. Garman

Third Advisor

Michael J. Knapp

Fourth Advisor

Peter Chien

Subject Categories

Biochemistry, Biophysics, and Structural Biology | Molecular Biology | Radiochemistry

Abstract

Caspases are the cysteine proteases that facilitate the fundamental pathway of programmed cell death or apoptosis. The activation and function of these powerful enzymes are tightly regulated to ensure the faithful execution of apoptosis and prevent untimely cell death. Many deadly human diseases such as cancer, neurodegeneration and autoimmune disorders have been associated with defective activation and faulty regulation of caspases. As such, caspases are considered as attractive drug targets, which when properly controlled, can lead to effective therapeutics for apoptosis-related diseases. Thus, comprehensive investigations of the structure, function and regulation of caspases are necessary to understand the complex mechanisms by which caspases are controlled in order to harness their potential for therapeutic purposes. This dissertation details the studies on the regulation of caspase-9 by phosphorylation mediated by the kinases PKA and c-Abl. Complementary approaches of biochemistry, structural biology and cell biology were utilized to elucidate the divergent mechanisms by which these kinases inhibit caspase-9 function. A critical residue was revealed to be a hotspot for inactivation upon PKA phosphorylation, utilizing two different mechanisms to silence caspase-9 activity. In addition, a novel site of phosphorylation by c-Abl that leads to inactivation was uncovered and is unique to caspase-9. These findings contribute to the growing information about caspases and kinases that will aid in the development of therapeutic strategies for apoptosis-related diseases.

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