Physical Sciences and Mathematics Commons^™

Allosteric Regulation Of Caspase-6 Proteolytic Activity, Elih M. Velazquez-Delgado

Open Access Dissertations

Caspases are cysteine proteases best known for their controlling roles in apoptosis and inflammation. Caspase-6 has recently been shown to play a key role in the cleavage of neurodegenerative substrates that causes Huntington and Alzheimer's Disease, heightening interest in caspase-6 and making it a drug target. All thirteen human caspases have related specificities for binding and cleaving substrate, so achieving caspase-specific regulation at the active site has been extremely challenging if not impossible. We have determined the structures of four unliganded forms of caspase-6, which attain a novel helical structure not observed in any other caspases. In this conformation, rotation …

Regulation Of Caspase-9 By Natural And Synthetic Inhibitors, Kristen L. Huber

Open Access Dissertations

Tight regulation of caspase-9, a key initiator of apoptosis, is required to uphold cellular homeostasis. Although it is controlled on a multifactorial level, misregulation of this process does occur, which is a characteristic of a variety of diseases from ischemic injury to cancer. Therefore it remains important to gain a detailed understanding of the mechanisms behind native caspase-9 regulatory pathways and harness these mechanisms for therapeutic purposes.

Based on known mechanisms, such as the unique inhibitory complex of caspase-9 and XIAP-BIR3, development of synthetic regulators can be envisioned, while other mechanisms such as zinc-mediated inhibition and CARD activation of caspse-9 …