Caspase nomenclature and classification

The observation that ced-3, a gene that is essential for apoptosis in the nematode Caenorhabditis elegans, encodes a polypeptide with extensive homology to the cysteine protease interleukin-1 p-converting enzyme (ICE) (8) prompted intensive investigation into the potential role of this family of proteases in various models of apoptosis. To date, 13 mammalian members of this family have been described, 11 in humans (1). A list of the known human caspases, along with their old names, molecular weights, and sequence preferences, is found in Table 1.

All of these enzymes share several properties. First, they are cysteine-dependent proteases that cleave polypeptides on the carboxyl side of aspartate residues. This activity led to the current designation of these enzymes as 'caspases' (9). Second, each of these enzymes is an a2fi2 tetramer consisting of two 17-20 kDa large subunits and two 10-12 kDa small subunits. Finally, each of the caspases is synthesized as a zymogen that encodes a prodomain, a large subunit, and a small subunit. Activation of these zymogens (Figure 1) involves proteolytic cleavage between the large and small subunits, followed by removal of the prodomain (1). Caspases themselves and the serine protease granzyme B are currently the only enzymes known to be capableof catalysing this activation process under physiological conditions (10-12).

Based on either sequence homology or function (1), these enzymes can be further divided into at least two broad categories, 'initiator' caspases and 'effector' caspases. Initiator caspases catalyse the cleavage of other caspases, thereby initiating a caspase cascade (1, 13). The initiator caspases typically contain long prodomains that interact with other intracellular components. For example, the prodomains of caspases-8 and -10 contain structural motifs

Large Small

Prodomain subunit subunit ^ ■

Procaspase Active caspase

Large Small

Prodomain subunit subunit ^ ■

Procaspase Active caspase

Initiator caspases

Effector caspases

Death receptor-associated:

8,10, possibly 2 Intrinsic pathway: 9

3,6 and 7

Figure 1. Schematic representation of caspase activation. As indicated in the text, caspases are synthesized as zymogens that contain three distinct domains. Activation involves cleavage between the large and small subunits followed by removal of the prodomain (1). Several of the caspases that have long prodomains serve as initiator caspases at the apex of protease cascades initiated by death receptors or endogenous signals (1). In contrast, the caspases with short prodomains appear to be responsible for cleavage of most of the substrates undergoing proteolysis during apoptosis.

Figure 1. Schematic representation of caspase activation. As indicated in the text, caspases are synthesized as zymogens that contain three distinct domains. Activation involves cleavage between the large and small subunits followed by removal of the prodomain (1). Several of the caspases that have long prodomains serve as initiator caspases at the apex of protease cascades initiated by death receptors or endogenous signals (1). In contrast, the caspases with short prodomains appear to be responsible for cleavage of most of the substrates undergoing proteolysis during apoptosis.

known as death effector domains (DEDs) that can interact with the homologous domains on adaptor proteins such as FADD/MORT1 (1,13). Likewise, a caspase recruitment domain (CARD) found in the prodomain of caspase-9 appears to promote interactions with other cytoplasmic components (e.g. the Apaf 1/cytochrome c complex) (14,15). According to one current model, the protein-protein interactions between prodomains and their interacting partners result in the juxtaposition of multiple procaspase molecules. Because these zymogens have low levels of intrinsic catalytic activity, this induced proximity allows one procaspase molecule to activate a neighbouring molecule in an 'autocatalytic' fashion (1).

Once activated, the initiator caspases are then able to cleave, and thereby activate, caspases that contain short prodomains, i.e. procaspases-3, -6, and -7 (1, 13). These so-called effector caspases cleave a variety of substrates throughout the cell (Table 2), thereby setting into motion the biochemical and morphological changes that constitute the apoptotic process (1).

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