| Apoptosis, or programmed cell death (PCD), is an evolutionarily conserved, genetically controlled, active form of cellular suicide encoded by an endogenous program that can be triggered by either internal or external cues. Apoptosis is essential for the development and homeostasis of multicellular organisms and functions as a major defense mechanism for the host by deleting nonfunctional, damaged and harmful cells. The morphological alterations of PCD include cellular shrinkage, membrane blebbing, and chromatin condensation. Derangements of apoptosis contribute to the pathogenesis of several human diseases including cancer, acquired immunodeficiency syndrome and neurodegenerative disorders.;A variety of signals, transduced through distinct signal transduction pathways, converge into a common cell death machinery in which the effector arm is composed by the ICE/CED-3 cysteine proteases (caspases). Caspases are synthesized as the inactive polypeptide precursors (zymogens), each composed of a prodomain, which is cleaved to activate the protease, and a large and small catalytic subunits. The coupling of these 'death' proteases to the signalling pathways is likely mediated by adaptor molecules that contain protein-protein interaction motifs. In this dissertation, using the strategy of homology search, three novel molecules involved in the cell death pathway were cloned and characterized. ICE-LAP3 and ICE-LAP6 are cysteine proteases belonging to the ICE/CED-3 family. RAIDD, is an adaptor molecule possessing a bipartite architecture. The C-terminal death domain of RAIDD specifically binds RIP through the death domain interaction. The N-terminal domain of RAIDD has statistically significant homology to the prodomain of two ICE/ced-3 family members, human caspase-2 and Caenorhabditis elegans CED-3. Through a homophilic interaction between the homologous regions, RAIDD recruits caspase-2, thereby serving as a direct link between the death receptor signalling pathway and the caspase cascade. |
