There are some conditions, such as cancer, in which it would be desirable to “turn on”
apoptosis, hastening the death of the malignant cell. There are other degenerative
conditions, such as Alzheimer’s disease, in which it would be desirable to “turn off”
apoptosis, prolonging the life of cells. Caspases are a family of proteins that are one of
the main effectors of apoptosis.
Because they are central to apoptosis, the caspases have emerged as important
prospects for drug discovery targets. The term caspase comes from cysteine protease
withaspartic acid specificity. The family is defined by sequence homology and conser-
vation of catalytic and substrate recognition residues. Caspases are present in all cells
as latent enzymes, called zymogens because they are inactive pro-forms of proteins. In
order to become biologically active, caspases must be activated. Typically, activation
occurs when two caspase proteins associate with each other (homodimerization) and
then use their own catalytic enzymatic portions to cleave themselves into subunits
via cleavage at internal aspartates (autoproteolysis). Alternatively, a caspase enzyme
can be cleaved into subunits by another caspase. Since all caspases are thiol-proteases,
they cleave at the carboxyl terminal of aspartate residues. Functionally, there are two
groups of caspases:
- Caspases involved in apoptosis
- Caspases involved in immunoregulation via cytokines
This section will focus on the pro-apoptotic caspases. Cytokines and their involvement
in immune regulation are discussed in chapter 6.
The caspases that are involved in apoptosis may be further classified as either initia-
torsoreffectors. Induction of apoptosis via death receptorsresults in the activation of
an initiator caspase. Caspases-8, -9, and -10 are initiators because they initiate the cas-
cade of biochemical events that culminates in apoptosis. Caspases-3, -6, and -7 propa-
gate this cascade (the so-called doomsday signal), thus functioning as effectors.
Although there is some overlap, caspases-1, -4, -5, -11, -12, and -13 are involved in pro-
cessing cytokines, thus influencing immunoregulation. The various caspases are listed
in table 8.2.
Crystal structures for a number of these caspases have been determined. Activated
caspase-3 has twofold symmetry. Caspase-3 has a protein core composed of a
12-strandedβ-sheet, surrounded by ten α-helices. There are two active sites, each
residing on an opposite protein side. Each active site is composed of a large subunit,
ENDOGENOUS MACROMOLECULES 501Table 8.1 Comparison of Apoptosis and Necrosis
Characteristic Apoptosis Necrosis
- Source of death-inducing trigger Internal External
- Reversibility No Sometimes
- Appearance of dying cells Shrink by 50% Swell during death process
- Integrity of cell membrane Usually intact Frequently ruptured
- Morphology of Nucleus Fragmented No or little change
- Structure of chromatin Condensed Minor changes only