The effector proteases in the apoptotic pathway, the caspases, are so named because they contain a key cysteine residue in the catalytic site and selectively cleave proteins at sites just C-terminal to aspartate residues. Caspases work as homodimers, with one domain of each stabilizing the active site of the other. The principal caspase in C. elegans is CED-3, while humans have 14 different caspases. All caspases are initially made as procaspases; most require a proteolytic cleavage to become active. In vertebrates, initiator caspases (e.g., caspase-9) are activated by dimerization induced by binding to other types of proteins (e.g., Apaf-1), which help the initiator caspases to aggregate. Activated initiator caspases cleave effector caspases (e.g., caspase-3) to activate them; in this way, the proteolytic activity of the few activated initiator caspases becomes rapidly and hugely increased by activation of the effector caspases, leading to a massive increase in the total caspase activity level in the cell (see Figure 21-35) and cell death. Procaspases preexist in large enough numbers to accomplish the digestion of much of the cellular protein when activated by the small number of molecules that constitute the initiation signal. The various effector caspases recognize and cleave short amino acid sequences in many different target proteins. They differ in their preferred target sequences. Their specific intracellular targets include proteins of the nuclear lamina and cytoskeleton whose cleavage leads to the demise of a cell.

As we learned in Chapter 7 (see page 282), the phospholipid phosphatidylserine is normally found in the inner, cytosolic leaflet of the plasma membrane. During apoptosis, increasing amounts of phosphatidylserine are found in the exoplasmic leaflet, where it acts as an “eat me” signal: it binds to a receptor-like protein on the surface of a neighboring cell that initiates engulfment. The multispanning, ubiquitously expressed C. elegans plasma membrane protein CED-8 and its mammalian homolog Xkr-8 are required for exposure of phosphatidylserine on the cell surface. These phospholipid flippases (see Figure 11-16) are normally inactive, but are activated by a very specific cleavage catalyzed by caspase-3 or caspase-7 (see Figure 21-35) during apoptosis.