The major function of the initiator caspases is to activate the executioner caspases. These normally exist as inactive dimers. When they are cleaved by an initiator caspase at a site in the protease domain, the active site is rearranged from an inactive to an active conformation. One initiator caspase complex can activate many executioner caspases, resulting in an amplifying proteolytic cascade. Once activated, executioner caspases catalyze the widespread protein cleavage events that kill the cell.
Various experimental approaches have led to the identification of over a thousand proteins that are cleaved by caspases during apoptosis. Only a few of these proteins have been studied in any detail. These include the nuclear lamins, the cleavage of which causes the irreversible breakdown of the nuclear lamina (discussed in Chapter 12). Another target is a protein that normally holds a DNA-degrading endonuclease in an inactive form; its cleavage frees the endonuclease to cut up the DNA in the cell nucleus (Figure 18–4). Other target proteins include components of the cytoskeleton and cell–cell adhesion proteins that attach cells to their neighbors; the cleavage of these proteins helps the apoptotic cell to round up and detach from its neighbors, making it easier for a neighboring cell to engulf it, or, in the case of an epithelial cell, for the neighbors to extrude the apoptotic cell from the cell sheet. The caspase cascade is not only destructive and self-amplifying but also irreversible, so that once a cell starts out along the path to destruction, it cannot turn back.
How is the initiator caspase first activated in response to an apoptotic signal? The two best-understood activation mechanisms in mammalian cells are called the extrinsic pathway and the intrinsic, or mitochondrial, pathway. Each uses its own initiator caspase and activation system, as we now discuss.
Figure 18–3 Caspase activation during apoptosis. An initiator caspase contains a protease domain in its carboxy-terminal region and a small protein interaction domain near its amino terminus. It is initially made in an inactive, monomeric form, sometimes called procaspase. Apoptotic signals trigger the assembly of adaptor proteins carrying multiple binding sites for the caspase amino-terminal domain. Upon binding to the adaptor proteins, the initiator caspases dimerize and are thereby activated, leading to cleavage of a specific site in their protease domains. Each protease domain is then rearranged into a large and small subunit. In some cases (not shown), the adaptor-binding domain of the initiator caspase is also cleaved (see Figure 18–5). Executioner caspases are initially formed as inactive dimers. Upon cleavage at a site in the protease domain by an initiator caspase, the executioner caspase dimer undergoes an activating conformational change. the executioner caspases then cleave a variety of key proteins, leading to the controlled death of the cell.