Mammalian caspases: Structure, activation, substrates, and functions during apoptosis

Apoptosis is a genetically programmed, morphologically distinct form of cel l death that can be triggered by a variety of physiological and pathologica l stimuli. Studies performed over the past 10 years have demonstrated that proteases play critical roles in initiation and execution of this process. The caspases, a family of cysteine-dependent aspartate-directed proteases, are prominent among the death proteases. Caspases are synthesized as relati vely inactive zymogens that become activated by scaffold-mediated transacti vation or by cleavage via upstream proteases in an intracellular cascade. R egulation of caspase activation and activity occurs at several different le vels: (a) Zymogen gene transcription is regulated; (b) antiapoptotic member s of the Bcl-2 family and other cellular polypeptides block proximity-induc ed activation of certain procaspases; and (c) certain cellular inhibitor of apoptosis proteins (cIAPs) can bind to and inhibit active caspases. Once a ctivated, caspases cleave a variety of intracellular polypeptides, includin g major structural elements of the cytoplasm and nucleus, components of the DNA repair machinery, and a number of protein kinases. Collectively, these scissions disrupt survival pathways and disassemble important architectura l components of the cell, contributing to the stereotypic morphological and biochemical changes that characterize apoptotic cell death.