Apoptosis is a highly regulated process that is essential for normal development and homeostasis of multicellular organisms. During viral infection, apoptosis is also a central point of interplay between the virus and the host. The characteristic features of apoptotic cell death are realized through the action of caspases, a family of conserved novel cysteine proteases. Both viral and cellular proteins have been identified that regulate apoptosis through caspase inhibition. Most notably, the p35 protein from baculoviruses is an effective and wide-spectrum caspase inhibitor that blocks apoptosis induced by numerous stimuli and in diverse organisms. Transgenic expression of p35 shows immense promise in controlling degenerative diseases. The inhibitors of apoptosis proteins (IAPs) comprise the largest family of protein caspase inhibitors, of which the X-linked IAP (XIAP) is the prototypical member. XIAP contains three tandem BIR repeats and a RING domain and exhibits specific anti-caspase activity. The involvement of IAPs in human diseases has also been suggested. A thorough understanding of caspase inhibition by protein caspase inhibitors requires structural studies of caspase/inhibitor complexes. In this proposal, we intend to determine crystal structures of several such complexes and to complement these structural studies with biochemical and mutational experiments.
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