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. Cysteine is a naturally occurring amino acid which has a thiol group and is found in most proteins, though only in small quantities. ... Proteases (proteinases, peptidases, or proteolytic enzymes) are enzymes that break peptide bonds between amino acids of proteins. ... Ribbon diagram of the enzyme TIM, surrounded by the space-filling model of the protein. ... A representation of the 3D structure of myoglobin, showing coloured alpha helices. ... Aspartic acid (Asp), also known as aspartate, the name of its anion, is one of the 20 natural proteinogenic amino acids which are the building blocks of proteins. ... Cells in culture, stained for keratin (red) and DNA (green). ... A cell undergoing apoptosis. ... Views of a Foetus in the Womb, Leonardo da Vinci, ca. ... ... Cytokines are small protein molecules that are the core of communication between immune system cells, and even between immune system cells and cells belonging to other tissue types. ... Tumor (American English) or tumour (British English) originally means swelling, and is sometimes still used with that meaning. ... In medicine, ischemia (Greek ισχαιμία, isch- is restriction, hema or haema is blood) is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. ...

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.

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. Translation is the second process of protein biosynthesis (part of the overall process of gene expression). ... Caspase recruitment domains, or CARD domains, are interaction motifs found in a wide array of proteins, typically those involved in processes relating to inflammation and apoptosis. ...

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. Granzymes are exogenous serine proteases that are released by cytoplasmic granules within cytotoxic T cells and natural killer cells. ... T cells are a subset of lymphocytes that play a large role in the immune response. ... The FAS ligand or FasL is a type II transmembrane protein that belongs to the tumor necrosis factor (TNF) family. ... A country trail, formed by wheels of vehicles. ... In medicine, tumor necrosis factor alpha (TNFα, cachexin or cachectin) is an important cytokine involved in systemic inflammation and the acute phase response. ... The apoptosome is a big multi-protein structure formed in the process of apoptosis. ... Cytochrome c, or cyt c (horse heart: PDB 1HRC) is a small heme protein found loosely associated with the inner membrane of the mitochondrion. ... B cell lymphoma (Bcl)-2 is a mammalian protein family whose members govern mitochondrial membrane permeabilisation (MMP), a key event in apoptosis. ... Positive feedback is a feedback system in which the system responds to the perturbation in the same direction as the perturbation (It is sometimes referred to as cumulative causation). ...

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. A lamin is a fibrous protein that gives the cell nucleus its shape. ...

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. H. Robert Horvitz is an American biologist best known for his research on the nematode worm Caenorhabditis elegans. ... Classes Adenophorea    Subclass Enoplia    Subclass Chromadoria Secernentea    Subclass Rhabditia    Subclass Spiruria    Subclass Diplogasteria The nematodes or roundworms (Phylum Nematoda from Gr. ... Binomial name Caenorhabditis elegans Wild-type C. elegans hermaphrodite stained to highlight the nuclei of all cells Caenorhabditis elegans () is a free-living nematode (a roundworm), about 1 mm in length, which lives in a temperate soil environment. ... 1993 (MCMXCIII) was a common year starting on Friday of the Gregorian calendar and marked the Beginning of the International Decade to Combat Racism and Racial Discrimination (1993-2003). ... Orders Multituberculata (extinct) Palaeoryctoides (extinct) Triconodonta (extinct) Subclass Australosphenida Ausktribosphenida Monotremata Subclass Eutheria (excludes extinct ancestors) Afrosoricida Anagaloidea (extinct) Arctostylopida (extinct) Artiodactyla Carnivora Cetacea Chiroptera Cimolesta (extinct) Cingulata Creodonta (extinct) Condylarthra (extinct) Dermoptera Desmostylia (extinct) Dinocerata (extinct) Embrithopoda (extinct) Hyracoidea Insectivora Lagomorpha Leptictida (extinct) Litopterna (extinct) Macroscelidea Mesonychia (extinct) Notoungulata... Binomial name Drosophila melanogaster Meigen, 1830 Drosophila melanogaster (from the Greek for black-bellied dew-lover) is a dipteran (two-winged) insect, and is the species of fruit fly that is most commonly used in genetic experiments; it is among the most important model organisms. ... 1996 (MCMXCVI) was a leap year starting on Monday of the Gregorian calendar, and was designated the International Year for the Eradication of Poverty. ...

For a good overview of the discovery of not just caspases but other aspects of apoptosis see articles by Danial and Korsmeyer,^[1] Yuan and Horvitz,^[2] and by Li et al.^[3] in the January 23rd 2004 edition of the journal 'Cell'. Cell is a bi-monthly peer-reviewed scientific journal which publishes novel research in any area of experimental biology that is significant outside its field. ...

See also

• Apoptosis
• Bcl-2
• Apoptosome

A cell undergoing apoptosis. ... B cell lymphoma (Bcl)-2 is a mammalian protein family whose members govern mitochondrial membrane permeabilisation (MMP), a key event in apoptosis. ... The apoptosome is a big multi-protein structure formed in the process of apoptosis. ...

References

1. ^ Danial, N. N., Korsmeyer, S. J. (January 2004). "Cell Death: Critical Control Points". Cell 116: 205-219. Retrieved on 2006-11-06.
2. ^ 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.
3. ^ Li, P., et al. (January 2004). "Mitochondrial Activation of Apoptosis". Cell 116: 57-59. Retrieved on 2006-11-06.

2006 (MMVI) is a common year starting on Sunday of the Gregorian calendar. ... November 6 is the 310th day of the year (311th in leap years) in the Gregorian Calendar, with 55 days remaining. ... 2006 (MMVI) is a common year starting on Sunday of the Gregorian calendar. ... November 6 is the 310th day of the year (311th in leap years) in the Gregorian Calendar, with 55 days remaining. ... 2006 (MMVI) is a common year starting on Sunday of the Gregorian calendar. ... November 6 is the 310th day of the year (311th in leap years) in the Gregorian Calendar, with 55 days remaining. ...

External links

• The caspase gallery