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455  structures 992  species 2  interactions 4033  sequences 280  architectures

Family: Peptidase_C14 (PF00656)

Summary: Caspase domain

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Caspase Edit Wikipedia article

Caspase domain
PDB 1ice EBI.jpg
Structure of interleukin-1 beta-converting enzyme.[1]
Identifiers
Symbol Peptidase_C14
Pfam PF00656
Pfam clan CL0093
InterPro IPR002398
PROSITE PS50208
MEROPS C14
SCOP 1ice
SUPERFAMILY 1ice

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.[2]

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[edit]

As of November 2009, twelve caspases have been identified in humans.[3] 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,[4] are not currently classified as initiator or effector in MeSH,[5] because they are inflammatory enzymes that, in concert with CASP1, are involved in T-cell maturation.

Caspase cascade[edit]

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 -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 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:

Overview of signal transduction pathways involved in apoptosis.

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.[1]

Discovery of caspases, functions[edit]

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.[6] 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.[2] 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.

For the discovery of caspases and other aspects of apoptosis, see articles by Danial and Korsmeyer,[7] Yuan and Horvitz,[8] and by Li et al.[9] in the January 23, 2004 edition of the journal Cell.

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.[10]

See also[edit]

References[edit]

  1. ^ 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. 
  2. ^ a b 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. 
  3. ^ HUGO Gene Nomenclature Committee
  4. ^ 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]
  5. ^ NIH Medical Subject Headings
  6. ^ 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. 
  7. ^ . 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. 
  8. ^ 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. 
  9. ^ 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. 
  10. ^ 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. 

External links[edit]

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Literature references

  1. 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

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].

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan Peptidase_CD (CL0093), which contains the following 9 members:

CHAT GVQW Peptidase_C11 Peptidase_C13 Peptidase_C14 Peptidase_C25 Peptidase_C50 Peptidase_C80 Raptor_N

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

  Seed
(115)
Full
(4033)
Representative proteomes NCBI
(4284)
Meta
(706)
RP15
(653)
RP35
(1049)
RP55
(1463)
RP75
(1901)
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Format an alignment

  Seed
(115)
Full
(4033)
Representative proteomes NCBI
(4284)
Meta
(706)
RP15
(653)
RP35
(1049)
RP55
(1463)
RP75
(1901)
Alignment:
Format:
Order:
Sequence:
Gaps:
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We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

  Seed
(115)
Full
(4033)
Representative proteomes NCBI
(4284)
Meta
(706)
RP15
(653)
RP35
(1049)
RP55
(1463)
RP75
(1901)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

Pfam alignments:

HMM logo

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Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Bateman A & Pfam-B_2524 (Release 8.0)
Previous IDs: ICE_p20;
Type: Domain
Author: Bateman A
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 information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 21.4 21.4
Trusted cut-off 21.4 21.4
Noise cut-off 21.3 21.3
Model length: 248
Family (HMM) version: 17
Download: download the raw HMM for this family

Species distribution

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Interactions

There are 2 interactions for this family. More...

BIR Peptidase_C14

Structures

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.

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