Summary: Caspase domain
This is the Wikipedia entry entitled "Caspase". More...
The Wikipedia text that you see displayed here is a download from Wikipedia. This means that the information we display is a copy of the information from the Wikipedia database. The button next to the article title ("Edit Wikipedia article") takes you to the edit page for the article directly within Wikipedia. You should be aware you are not editing our local copy of this information. Any changes that you make to the Wikipedia article will not be displayed here until we next download the article from Wikipedia. We currently download new content on a nightly basis.
Does Pfam agree with the content of the Wikipedia entry ?
Pfam has chosen to link families to Wikipedia articles. In some case we have created or edited these articles but in many other cases we have not made any direct contribution to the content of the article. The Wikipedia community does monitor edits to try to ensure that (a) the quality of article annotation increases, and (b) vandalism is very quickly dealt with. However, we would like to emphasise that Pfam does not curate the Wikipedia entries and we cannot guarantee the accuracy of the information on the Wikipedia page.
Editing Wikipedia articles
Before you edit for the first time
Wikipedia is a free, online encyclopedia. Although anyone can edit or contribute to an article, Wikipedia has some strong editing guidelines and policies, which promote the Wikipedia standard of style and etiquette. Your edits and contributions are more likely to be accepted (and remain) if they are in accordance with this policy.
You should take a few minutes to view the following pages:
How your contribution will be recorded
Anyone can edit a Wikipedia entry. You can do this either as a new user or you can register with Wikipedia and log on. When you click on the "Edit Wikipedia article" button, your browser will direct you to the edit page for this entry in Wikipedia. If you are a registered user and currently logged in, your changes will be recorded under your Wikipedia user name. However, if you are not a registered user or are not logged on, your changes will be logged under your computer's IP address. This has two main implications. Firstly, as a registered Wikipedia user your edits are more likely seen as valuable contribution (although all edits are open to community scrutiny regardless). Secondly, if you edit under an IP address you may be sharing this IP address with other users. If your IP address has previously been blocked (due to being flagged as a source of 'vandalism') your edits will also be blocked. You can find more information on this and creating a user account at Wikipedia.
If you have problems editing a particular page, contact us at email@example.com and we will try to help.
The community annotation is a new facility of the Pfam web site. If you have problems editing or experience problems with these pages please contact us.
Caspase Edit Wikipedia article
Structure of interleukin-1 beta-converting enzyme.
Caspases, or cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases are a family of cysteine proteases that play essential roles in apoptosis (programmed cell death), necrosis, and inflammation.
Caspases are essential in cells for apoptosis, or 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 lymphocytes. Failure of apoptosis is one of the main contributions to tumour development and autoimmune diseases; this, coupled with the unwanted apoptosis that occurs with ischemia or Alzheimer's disease, has stimulated interest in caspases as potential therapeutic targets since they were discovered in the mid-1990s.
Types of caspase proteins
As of November 2009[update], twelve caspases have been identified in humans. There are two types of apoptotic caspases: initiator (apical) caspases and effector (executioner) caspases. Initiator caspases (e.g., CASP2, CASP8, CASP9, and CASP10) cleave inactive pro-forms of effector caspases, thereby activating them. Effector caspases (e.g., CASP3, CASP6, CASP7) in turn cleave other protein substrates within the cell, to trigger the apoptotic process. The initiation of this cascade reaction is regulated by caspase inhibitors.
CASP4 and CASP5, which are overexpressed in some cases of vitiligo and associated autoimmune diseases caused by NALP1 variants, are not currently classified as initiator or effector in MeSH, because they are inflammatory enzymes that, in concert with CASP1, are involved in T-cell maturation.
Caspases are regulated at a post-translational level, ensuring that 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 caspase-9) or a death effector domain (DED) (caspases-8 and caspase-10) that enables the caspases to interact with other molecules that regulate their activation. These molecules respond to stimuli that cause the clustering of the initiator caspases. Such clustering allows them to activate automatically, so that they can proceed to activate the effector caspases.
The caspase cascade can be activated by:
- granzyme B (released by cytotoxic T lymphocytes and NK cells), which is known to activate caspase-3 and -7
- death receptors (like Fas, TRAIL receptors and TNF receptor), which can activate caspase-8 and -10
- the apoptosome (regulated by cytochrome c and the Bcl-2 family), which activates caspase-9.
Some of the final targets of caspases include:
- nuclear lamins
- ICAD/DFF45 (inhibitor of caspase activated DNase or DNA fragmentation factor 45)
- PARP (poly-ADP ribose polymerase)
- PAK2 (P 21-activated kinase 2).
The role of caspase substrate cleavage in the morphology of apoptosis is not clear. However, ICAD/DFF45 acts to restrain 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' in apoptotic cells.
In 2009, Queensland researchers announced caspase 1 and 3 in macrophages are regulated by p202 (a double-stranded DNA binding protein) reducing caspase response, and AIM2 (another double-stranded DNA binding protein) increasing caspase activation.
Discovery of caspases, functions
H. Robert Horvitz initially established the importance of caspases in apoptosis and found that the ced-3 gene is 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 is 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. Other mammalian caspases were subsequently identified, in addition to caspases in organisms such as fruit fly Drosophila melanogaster.
Researchers decided upon the nomenclature of the caspase in 1996. In many instances, a particular caspase had been identified simultaneously by more than one laboratory, who would each give the protein a different name. For example, caspase 3 was variously known as CPP32, apopain and Yama. Caspases, therefore, were numbered in the order in which they were identified. ICE was, therefore, renamed as caspase 1. ICE was the first mammalian caspase to be characterised because of its similarity to the nematode death gene ced-3, but it appears that the principal role of this enzyme is to mediate inflammation rather than cell death.
Recent studies have demonstrated that caspase proteases are also regulators of non-death functions, the most notable ones being those involving the maturation of a wide variety of cells such as red blood cells and skeletal muscle myoblasts.
- The Proteolysis Map
- Programmed cell death
- Wilson KP, Black JA, Thomson JA, et al. (July 1994). "Structure and mechanism of interleukin-1 beta converting enzyme". Nature 370 (6487): 270–5. doi:10.1038/370270a0. PMID 8035875.
- Alnemri ES, Emad S; et al. (1996). "Human ICE/CED-3 Protease Nomenclature". Cell 87 (2): 171. doi:10.1016/S0092-8674(00)81334-3. PMID 8861900. Retrieved 6 March 2011.
- HUGO Gene Nomenclature Committee
- Gregersen, P.K. (22 March 2007). "Modern genetics, ancient defenses, and potential therapies". N Engl J Med. 356 (12): 1263–6. doi:10.1056/NEJMe078017. PMID 17377166.[PMID 17377166]
- NIH Medical Subject Headings
- Yuan, J et al. (1993). "The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme". Cell 75 (4): 641–652. doi:10.1016/0092-8674(93)90485-9. PMID 8242740.
- . Danial, N. N.; Korsmeyer, S. J. (January 2004). "Cell Death: Critical Control Points". Cell 116 (2): 205–219. doi:10.1016/S0092-8674(04)00046-7. PMID 14744432. Retrieved 2006-11-06.
- Yuan, J.; Horvitz, H. R. (January 2004). "A First Insight into the Molecular Mechanisms of Apoptosis". Cell 116 (2 Suppl): 53–56. doi:10.1016/S0092-8674(04)00028-5. PMID 15055582. Retrieved 2006-11-06.
- Li, P.; et al. (January 2004). "Mitochondrial Activation of Apoptosis". Cell 116 (2 Suppl): 57–59. doi:10.1016/S0092-8674(04)00031-5. PMID 15055583. Retrieved 2006-11-06.
- Lamkanfi, M.; et al. (January 2007). "Caspases in cell survival, proliferation and differentiation". Cell Death and Differentiation 14 (1): 44–55. doi:10.1038/sj.cdd.4402047. PMID 17053807. Retrieved 2011-02-28.
- Eukaryotic Linear Motif resource motif class CLV_C14_Caspase3-7
- Apoptosis Video Demonstrates a model of a caspase cascade as it occurs in vivo.
- The Mechanisms of Apoptosis Kimball's Biology Pages. Simple explanation of the mechanisms of apoptosis triggered by internal signals (bcl-2), along the caspase-9, caspase-3 and caspase-7 pathway; and by external signals (FAS and TNF), along the caspase 8 pathway. Accessed 25 March 2007.
- Apoptosis & Caspase 7, PMAP-animation
- Caspases at the US National Library of Medicine Medical Subject Headings (MeSH)
- Tumors Beware (from Beaker Blog)
Caspase domain Provide feedback
No Pfam abstract.
Wilson KP, Black JA, Thomson JA, Kim EE, Griffith JP, Navia MA, Murcko MA, Chambers SP, Aldape RA, Raybuck SA, et al , Nature 1994;370:270-275.: Structure and mechanism of interleukin-1 beta converting enzyme. PUBMED:8035875 EPMC:8035875
Internal database links
|Similarity to PfamA using HHSearch:||Peptidase_C13 Raptor_N|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR011600
In the MEROPS database peptidases and peptidase homologues are grouped into clans and families. Clans are groups of families for which there is evidence of common ancestry based on a common structural fold:
- Each clan is identified with two letters, the first representing the catalytic type of the families included in the clan (with the letter 'P' being used for a clan containing families of more than one of the catalytic types serine, threonine and cysteine). Some families cannot yet be assigned to clans, and when a formal assignment is required, such a family is described as belonging to clan A-, C-, M-, N-, S-, T- or U-, according to the catalytic type. Some clans are divided into subclans because there is evidence of a very ancient divergence within the clan, for example MA(E), the gluzincins, and MA(M), the metzincins.
- Peptidase families are grouped by their catalytic type, the first character representing the catalytic type: A, aspartic; C, cysteine; G, glutamic acid; M, metallo; N, asparagine; S, serine; T, threonine; and U, unknown. The serine, threonine and cysteine peptidases utilise the amino acid as a nucleophile and form an acyl intermediate - these peptidases can also readily act as transferases. In the case of aspartic, glutamic and metallopeptidases, the nucleophile is an activated water molecule. In the case of the asparagine endopeptidases, the nucleophile is asparagine and all are self-processing endopeptidases.
In many instances the structural protein fold that characterises the clan or family may have lost its catalytic activity, yet retain its function in protein recognition and binding.
Cysteine peptidases have characteristic molecular topologies, which can be seen not only in their three-dimensional structures, but commonly also in the two-dimensional structures. These are peptidases in which the nucleophile is the sulphydryl group of a cysteine residue. Cysteine proteases are divided into clans (proteins which are evolutionary related), and further sub-divided into families, on the basis of the architecture of their catalytic dyad or triad [PUBMED:11517925].
This group of sequences represent the p20 (20kDa) and p10 (10kDa) subunits of caspases, which together form the catalytic domain of the caspase and are derived from the p45 (45 kDa) precursor (INTERPRO) [PUBMED:15226512].
Caspases (Cysteine-dependent ASPartyl-specific proteASE) are cysteine peptidases that belong to the MEROPS peptidase family C14 (caspase family, clan CD) based on the architecture of their catalytic dyad or triad [PUBMED:11517925]. Caspases are tightly regulated proteins that require zymogen activation to become active, and once active can be regulated by caspase inhibitors. Activated caspases act as cysteine proteases, using the sulphydryl group of a cysteine side chain for catalysing peptide bond cleavage at aspartyl residues in their substrates. The catalytic cysteine and histidine residues are on the p20 subunit after cleavage of the p45 precursor.
Caspases are mainly involved in mediating cell death (apoptosis) [PUBMED:10578171, PUBMED:10872455, PUBMED:15077141]. They have two main roles within the apoptosis cascade: as initiators that trigger the cell death process, and as effectors of the process itself. Caspase-mediated apoptosis follows two main pathways, one extrinsic and the other intrinsic or mitochondrial-mediated. The extrinsic pathway involves the stimulation of various TNF (tumour necrosis factor) cell surface receptors on cells targeted to die by various TNF cytokines that are produced by cells such as cytotoxic T cells. The activated receptor transmits the signal to the cytoplasm by recruiting FADD, which forms a death-inducing signalling complex (DISC) with caspase-8. The subsequent activation of caspase-8 initiates the apoptosis cascade involving caspases 3, 4, 6, 7, 9 and 10. The intrinsic pathway arises from signals that originate within the cell as a consequence of cellular stress or DNA damage. The stimulation or inhibition of different Bcl-2 family receptors results in the leakage of cytochrome c from the mitochondria, and the formation of an apoptosome composed of cytochrome c, Apaf1 and caspase-9. The subsequent activation of caspase-9 initiates the apoptosis cascade involving caspases 3 and 7, among others. At the end of the cascade, caspases act on a variety of signal transduction proteins, cytoskeletal and nuclear proteins, chromatin-modifying proteins, DNA repair proteins and endonucleases that destroy the cell by disintegrating its contents, including its DNA. The different caspases have different domain architectures depending upon where they fit into the apoptosis cascades, however they all carry the catalytic p10 and p20 subunits.
Caspases can have roles other than in apoptosis, such as caspase-1 (interleukin-1 beta convertase) (EC), which is involved in the inflammatory process. The activation of apoptosis can sometimes lead to caspase-1 activation, providing a link between apoptosis and inflammation, such as during the targeting of infected cells. Caspases may also be involved in cell differentiation [PUBMED:15066636].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||cysteine-type endopeptidase activity (GO:0004197)|
|Biological process||proteolysis (GO:0006508)|
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Loading domain graphics...
The members of this clan are all endopeptidase that have the catalytic dyad histidine followed by cysteine. The catalytic histidine is preceded by a block of hydrophobic residues and a glycine, where as the cysteine is preceded by a block of hydrophobic residues and a glutamine and an alanine. The members with a know structure adopt an alpha/beta fold .
The clan contains the following 9 members:CHAT GVQW Peptidase_C11 Peptidase_C13 Peptidase_C14 Peptidase_C25 Peptidase_C50 Peptidase_C80 Raptor_N
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- Pfam viewer
- an HTML-based viewer that uses DAS to retrieve alignment fragments on request
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
If you find these logos useful in your own work, please consider citing the following article:
Note: You can also download the data file for the tree.
Curation and family details
|Seed source:||Bateman A & Pfam-B_2524 (Release 8.0)|
|Number in seed:||115|
|Number in full:||4033|
|Average length of the domain:||230.40 aa|
|Average identity of full alignment:||15 %|
|Average coverage of the sequence by the domain:||47.36 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||17|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
How the sunburst is generated
Colouring and labels
Anomalies in the taxonomy tree
Missing taxonomic levels
Unmapped species names
Too many species/sequences
The tree shows the occurrence of this domain across different species. More...
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
There are 2 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Peptidase_C14 domain has been found. There are 455 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
Loading structure mapping...