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March 13th Seminar-Caspase Allostery and Cell Death



Topic:       Caspase Allostery and Cell Death

Speaker:  Prof. Clay Clark

     Professor and Interim Head

Department of Molecular and Structural Biochemistry

North Carolina State University


Caspase conformational states are important for their function in apoptosis. Although largely similar in structure, an important difference exists in the mechanism for enzyme activation between the initiator and effector caspases. In the case of initiator caspases (namely caspases 8, 9, and 10), the zymogen exists as a stable monomer, and upstream cell death signals lead to its localization to activation scaffolds. It is believed that, for the initiator caspases, the proteolytic processing that follows dimerization acts mainly to stabilize the dimer. In contrast, the zymogens of effector caspases (caspases 3, 6, and 7) are stable dimers, although they exhibit very little enzymatic activity, and cleavage of the IL by the initiator caspases results in full enzyme activation. We have shown that mutations in an allosteric site of the dimer interface of caspase-3 results in constitutive activation of the procaspase and that the activated procaspase efficiently kills cells. I will discuss the allosteric site in caspase-3 as well as conformational changes in the procaspase that lead to activation. I will also describe our efforts to understand dimerization in caspase-8 by redesigning the dimer interface. Using phage display and other techniques, we have identified peptides that bind to caspase-3 and affect activity, and the data suggest that one peptide may affect the function of caspase-3 during adaptive responses, that is, under conditions where low levels of caspase activity are important for cell differentiation.


Host:       Prof. Yigong Shi

Date:       10:10AM-11:10AM, Mar. 13 (Wednesday)

Venue:    B323, Medical Science Building



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