Caspase
From Wikipedia, the free encyclopedia
Caspases are a group of cysteine proteases, enzymes with a crucial cysteine residue that can cleave other proteins after an aspartic acid residue, a specificity which is unusual among proteases. The name "caspase" derives from this characteristic molecular function: cysteine-aspartic-acid-proteases. 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, and have been termed "executioner" proteins for their roles in the cell. Some caspases are also required in the immune system for the maturation of cytokines. Failure of apoptosis is one of the main contributions to tumour development and autoimmune diseases; this coupled with the unwanted apoptosis that occurs with ischaemia or Alzheimer's disease, has boomed the interest in caspases as potential therapeutic targets since they were discovered in the mid 1990s.
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[edit] Types of caspase proteins
There are two types of caspases: initiator caspases and effector caspases. Initiator caspases (e.g. caspase-8, caspase-9) cleave inactive pro-forms of effector caspases, thereby activating them; effector caspases (e.g. caspase-3, caspase-7) in turn cleave other protein substrates within the cell resulting in the apoptotic process. The initiation of this cascade reaction is regulated by caspase inhibitors. Twelve caspases have so far been identified in humans.
[edit] The caspase cascade
Caspases are regulated at a post-translational level, ensuring they can be rapidly activated. They are first synthesized as inactive pro-caspases, that consist of a prodomain, a small subunit and a large subunit. Initiator caspases possess a longer prodomain than the effector caspases, whose prodomain is very small. The prodomain of the initiator caspases contain domains such as a CARD domain (e.g. caspases-2 and -9) or a death effector domain (DED) (caspases-8 and -10) that enables the caspases to interact with other molecules that regulate their activation. These molecules respond to stimuli to cause the clustering of the initiator caspases which allows them to autoactivate so that they can then proceed to activate the effector caspases.
The caspase cascade can be activated by Granzyme B released by cytotoxic T lymphocytes which is known to activate caspase-3 and -7; death receptors (like FAS, TRAIL and TNF) which can activate caspase-8 and -10; and the apoptosome, regulated by cytochrome c and 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.
Some of the final targets of caspases include: nuclear lamins, ICAD/DFF45, poly(ADP)ribose polymerase (PARP) and PAK2. The exact contribution that the cleavage of many caspase substrates makes to the biochemistry and morphology of apoptosis is unclear. However, the function of ICAD/DFF45 is to restrain the enzyme CAD (Caspase Activated DNase). The cleavage and inactivation of ICAD/DFF45 by a caspase allows CAD to enter the nucleus and fragment the DNA, causing the characteristic 'DNA ladder' seen in apoptotic cells.
[edit] Discovery of caspases, their functions and roles
The importance of caspases to apoptosis and programmed cell death was originally established by Robert Horvitz and colleagues who found that the ced-3 gene was required for the cell death that took place during the development of the nematode C. elegans. Horvitz and his colleague Junying Yuan found in 1993 that the protein encoded by the ced-3 gene was a cysteine protease with similar properties to the mammalian interleukin-1-beta converting enzyme (ICE) (now known as caspase 1) which at the time was the only known caspase. Following this discovery, the other mammalian caspases, in addition to caspases in other organisms such as the fruit fly Drosophila melanogaster, were soon identified and characterised. A consortium of researchers in the field decided upon the caspase nomenclature early in 1996, as in many instances a particular caspase had been identified simultaneously by more than one lab, who would each give the protein a different name (e.g. caspase 3 was variously known as CPP32, apopain and Yama). The caspases are numbered in the order in which they were identified, hence the renaming of ICE to caspase 1. Ironically, although ICE was the first mammalian caspase to be characterised due to its similarity to the nematode death gene ced-3, it seems that the principal role for this enzyme is in mediating inflammation rather than in cell death.
For a good overview of the discovery of not just caspases but other aspects of apoptosis see articles by Danial and Korsmeyer,<ref>
Danial, N. N., Korsmeyer, S. J. (January 2004). "Cell Death: Critical Control Points". Cell 116: 205-219. Retrieved on 2006-11-06.
</ref> Yuan and Horvitz,<ref>
Yuan, J., Horvitz, H. R. (January 2004). "A First Insight into the Molecular Mechanisms of Apoptosis". Cell 116: 53-56. Retrieved on 2006-11-06.
</ref> and by Li et al.<ref>
Li, P., et al. (January 2004). "Mitochondrial Activation of Apoptosis". Cell 116: 57-59. Retrieved on 2006-11-06.
</ref> in the January 23rd 2004 edition of the journal 'Cell'.
[edit] See also
[edit] References
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