Caspases are a group of cysteine proteases, enzymes with a crucial cysteine residue that can cleave other proteins, after an aspartic acid residue. Caspases are essential in cells for apoptosis, one of the main types of programmed cell death in development and most other stages of adult life. Because of their role in tumor suppression and potential application to cancer prevention, interest in caspases has boomed since the 1990s.

Caspases derive their name from cysteine-aspartic-acid-proteases. There are two types of caspases: initiator caspases, which cleave inactive pro-forms of other caspases, and thus activate them. These latter caspases are known as efector caspases for they, in turn, start the apoptotic process per se by cleaving other enzymes. The initiation of that cascade reaction is usually blocked by caspase inhibitors. Induction of apoptosis thus means overexpression of the initial caspases, overcoming the inhibition.

These proteins are regulated at a post-translational level, ensuring they can be rapidly activated. They are first synthesized as immature pro-caspases, which exhibit a prodomain, a small subunit and a large subunit. The prodomain interacts with a CARD domain found in other proteins, which activates the caspase. Thus the pro-domain of initiator pro-caspases interacts with diverse proteins, while the pro-domain of effector pro-caspases interacts only with initiator caspases. Activation occurs when the prodomain-CARD domain interaction cleaves the pro-caspase, the prodomain is then lost and the large and small subunits form an heterodimer. Two heterodimers then bind forming a tetramer: the active form of a caspase enzyme.

The caspase cascade can be activated by Granzyme B released by cytotoxic T lymphocytes which is known to activate caspase-3, -7, -8 and -10; death receptors (like Fas , TRAIL and TNF) which can activate caspase-8 and -10; and the apoptosome , regulated by the Bcl-2 family, which activates caspase-9. Once this cascade is started, a positive feedback ensures the cell will inevitably undergo apoptosis: for example apoptosome-activated caspase-9 cleaves and activates caspase-3, this caspase-3 besides cleaving its target proteins, will also cleave more of caspase-9, which in turn will activate more of caspase-3.

There are 13 caspases known, some of the final targets of caspases include: nuclear lamins, ICAD and PAK2. The first two lose their function, while PAK2 is activated when cleaved by the caspases.

Information

Caspases were first identified as the enzyme that activates (converts) Interleukin 1-beta (ICE). It is activated by a protease, and the substrates include themselves and other caspases.

See also

• Apoptosis
• Bcl-2

External link

• The caspase gallery