Summary: Caspase recruitment domain
Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.
This is the Wikipedia entry entitled "CARD domain". 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.
CARD domain Edit Wikipedia article
|Caspase recruitment domain|
Structure of the RAIDD CARD.
Caspase recruitment domains, or Caspase activation and recruitment domains (CARDs), are interaction motifs found in a wide array of proteins, typically those involved in processes relating to inflammation and apoptosis. These domains mediate the formation of larger protein complexes via direct interactions between individual CARDs. CARD domains are found on a strikingly wide range of proteins, including helicases, kinases, mitochondrial proteins, caspases, and other cytoplasmic factors.
CARD domains are a subclass of protein motif known as the death fold, which features an arrangement of six to seven antiparallel alpha helices with a hydrophobic core and an outer face composed of charged residues. Other motifs in this class include the pyrin domain (PYD), death domain (DD), and death effector domain (DED), all of which also function primarily in regulation of apoptosis and inflammatory responses.
CARD domains in apoptosis
CARD domains were originally characterized based on their involvement in the regulation of caspase activation and apoptosis. The basic six-helix structure of the domain appears to be conserved as far back as the ced-3 and ced-4 genes in C. elegans, the organism in which several components of the apoptotic machinery were first characterized. CARD motifs are present on a number of proteins that promote apoptosis, primarily caspases 1,2,4,5,9, and 15 in mammals.
CARD domains in the mammalian immune response
IL-1 and IL-18 processing
A number of CARD proteins have been shown to play a role in regulating inflammation in response to bacterial and viral pathogens as well as to a variety of endogenous stress signals. Recently, studies on the NLR protein Ipaf-1 have provided insight into how CARD proteins participate in the immune response. Ipaf-1 features an N-terminal CARD domain, a nucleotide-binding domain, and C-terminal leucine-rich repeats (LRRs), thought to function in a similar fashion to those found in Toll-like receptors. The primary role of this molecule appears to be regulation of the proteolytic processing of pro-IL-1β and pro-IL-18 into their mature forms via association in a large complex known as the inflammasome. Upon activation of Ipaf-1 by the intracellular bacterium S. typhimurium or other stress signals, Ipaf-1 recruits a CARD-containing adapter termed ASC and caspase-1 in unknown stoichiometry via CARD-CARD association. This complex in turn leads to autoproteolytic activation of caspase-1 and subsequent IL-1β and IL-18 maturation.
Recently, a subset of CARD proteins has been shown to participate in recognition of intracellular double-stranded RNA, a common constituent of a number of viral genomes, including the para- and orthomyxoviridae and rhabdoviridae. Unlike NLRs, these proteins, termed RIG-I and MDA5, contain twin N-terminal CARD domains and C-terminal RNA helicase domains that directly interact with and process the double-stranded viral RNA. This processing makes the CARD domains available for interaction with the CARD motif of IPS-1/MAVS/VISA/Cardif, a downstream adapter anchored in the mitochondria. Although the interactions between IPS-1 and RIG-I/MDA-5 have been shown in vitro, the nature of the complex formed upon viral detection has not been characterized.
The adaptor protein VISA further activates the IKK-protein-kinase family members. Although the canonical IKK family members IKKa and IKKb are essential for virus-triggered NF-κB activation, the noncanonical IKK family members TBK1 and IKBKE are responsible for phosphorylating and activating IRF3 and IRF7 (Fitzgerald et al., 2003; Hemmi et al., 2004; Matsui et al., 2006). Various studies have also demonstrated the involvement of several other signaling components in virus-induced activation of NF-κB and/or IRF3, including TRAF3, TRAF6, TANK, NEMO(IKKg), TRADD, FADD, and RIP (Kawai et al., 2005; Michallet et al., 2008; Oganesyan et al., 2006; Saha et al., 2006; Xu et al., 2005; Zhao et al., 2007).
Because of their role as regulators of inflammation, constitutive activation of certain CARD proteins, either conferred by mutation or by constant presence of stress signals, has been suggested to play a causative role in a number of inflammatory syndromes. Gain-of-function mutations in the intracellular NOD2 protein has been linked to increased risk for Crohn's disease. Activating mutations in at least two related PYD-containing proteins, cryopyrin/CIAS-1 and pyrin/MEFV, have been linked to Muckle-Wells Syndrome and familial Mediterranean fever, respectively.
List of CARD containing proteins
- BIRC2 baculoviral Inhibitor of apoptosis (IAP) repeat-containing 2, also known as C-IAP1 
- BIRC3 baculoviral IAP repeat-containing 3, also known as C-IAP2 
- Caspase 1: caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase; ICE) 
- Caspase 2: caspase 2, apoptosis-related cysteine peptidase 
- Caspase 4: caspase 4, apoptosis-related cysteine peptidase 
- Caspase 5: caspase 5, apoptosis-related cysteine peptidase 
- Caspase 9: caspase 9, apoptosis-related cysteine peptidase 
- Caspase 12: caspase 12, apoptosis-related cysteine peptidase 
- Caspase 13: caspase 13, apoptosis-related cysteine peptidase 
- ICEBERG: caspase 1 inhibitor iceberg 
- Pseudo-ICE:Caspase-1 dominant-negative inhibitor Pseudo-ICE, also known as COP1 
- MDA-5: Melanoma differentiation-associated protein 5, also called Interferon-induced helicase C domain-containing protein 1 (IFIH1) 
- MAVS: Mitochondrial antiviral-signaling protein also known as CARD adapter inducing interferon-beta (Cardif/IPS-1) 
- CRADD: Caspase and RIP adapter with death domain also known as RIP-associated protein with a death domain (RAIDD) 
- RAIDD-2: Death adaptor molecule RAIDD-2 
- RIG-I: Retinoic acid-inducible gene 1 protein, also known as DEAD-box protein 58 (DDX58) 
- RIPK2: receptor-interacting serine-threonine kinase 2 (also called cardiak, RIP2 or RICK kinase) 
- BCL10: B-cell lymphoma/leukemia 10 protein 
- BINCA: Bcl10-interacting CARD protein or BinCARD, also called chromosome 9 open reading frame 89 (C9orf89) 
- CARD6: caspase recruitment domain family, member 6 
- CARD8/CARDINAL: caspase recruitment domain family, member 8 
- CARD9: caspase recruitment domain family, member 9 
- CARD10: caspase recruitment domain family, member 10 (also called CARMA3) 
- CARD11: caspase recruitment domain family, member 11 (also called CARMA1) 
- CARD14: caspase recruitment domain family, member 14 (also called CARMA2) 
- APAF1: apoptotic peptidase activating factor 1 (also called CED4) 
- GLAVA1: glavaris peptidase activating factor 1 (also called GLAV1) 
- IPAF: Ice protease-activating factor, also known as NLR family, card domain containing 4 (NLRC4), CARD, LRR, and NACHT-containing protein (CLAN) and Caspase recruitment domain-containing protein 12 (CARD12) 
- NOD1: nucleotide-binding oligomerization domain containing 1 
- NOD2: nucleotide-binding oligomerization domain containing 2 
- NLRC3: NOD-like receptor family CARD domain containing 3 
- NLRP1: NLR family, pyrin domain containing 1 (previously called NALP1) 
- NOL3: nucleolar protein 3 (apoptosis repressor with CARD domain) 
- PYCARD: PYD and CARD domain containing protein (also called ASC) 
- Chou JJ, Matsuo H, Duan H, Wagner G (July 1998). "Solution structure of the RAIDD CARD and model for CARD/CARD interaction in caspase-2 and caspase-9 recruitment". Cell 94 (2): 171–80. doi:10.1016/S0092-8674(00)81417-8. PMID 9695946.
- Hofmann K, Bucher P, Tschopp J (1997). "The CARD domain: a new apoptotic signalling motif". Trends Biochem Sci 22 (5): 155–6. doi:10.1016/S0968-0004(97)01043-8. PMID 9175472.
- Hiscott J; et al. (2006). "MasterCARD: a priceless link to innate immunity". Trends Mol Med 12 (2): 53–6. doi:10.1016/j.molmed.2005.12.003. PMID 16406812.
- Ting JP, Williams KL (2005). "The CATERPILLER family: an ancient family of immune/apoptotic proteins". Clin Immunol 115 (1): 33–7. doi:10.1016/j.clim.2005.02.007. PMID 15870018.
- Martinon F, Tschopp J (2004). "Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases". Cell 117 (5): 561–74. doi:10.1016/j.cell.2004.05.004. PMID 15163405.
- Hong GS, Junk YK (2002). "Caspase recruitment domain (CARD) as a bi-functional switch of caspase regulation and NF-kappaB signals". J Biochem Mol Biol 35 (1): 19–23. doi:10.5483/BMBRep.2002.35.1.019. PMID 16248965.
- Bouchier-Hayes L, Martin SJ (2002). "CARD games in apoptosis and immunity". EMBO Rep 3 (7): 616–21. doi:10.1093/embo-reports/kvf139. PMC 1084193. PMID 12101092.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Caspase recruitment domain Provide feedback
Motif contained in proteins involved in apoptotic signaling. Predicted to possess a DEATH (PF00531) domain-like fold .
Internal database links
|Similarity to PfamA using HHSearch:||CARD_2|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR001315
The caspase recruitment domain (CARD domain) is a homotypic protein interaction module composed of a bundle of six alpha-helices. CARD is related in sequence and structure to the death domain (DD, see INTERPRO) and the death effector domain (DED, see INTERPRO), which work in similar pathways and show similar interaction properties [PUBMED:11504623]. The CARD domain typically associates with other CARD-containing proteins, forming either dimers or trimers. CARD domains can be found in isolation, or in combination with other domains. Domains associated with CARD include: NACHT (INTERPRO) (in Nal1 and Bir1), NB-ARC (INTERPRO) (in Apaf-1), pyrin/dapin domains (INTERPRO) (in Nal1), leucine-rich repeats (INTERPRO) (in Nal1), WD repeats (INTERPRO) (in Apaf1), Src homology domains (INTERPRO), PDZ (INTERPRO), RING, kinase and DD domains [PUBMED:15226512].
CARD-containing proteins are involved in apoptosis through their regulation of caspases that contain CARDs in their N-terminal pro-domains, including human caspases 1, 2, 9, 11 and 12 [PUBMED:9175472]. CARD-containing proteins are also involved in inflammation through their regulation of NF-kappaB [PUBMED:12101092]. The mechanisms by which CARDs activate caspases and NF-kappaB involve the assembly of multi-protein complexes, which can facilitate dimerisation or serve as scaffolds on which proteases and kinases are assembled and activated.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Biological process||regulation of apoptotic process (GO:0042981)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- 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
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
Loading domain graphics...
The death domain superfamily is composed of three families: the death domain (DD); the death effector domain (DED) and the caspase recruitment domain (CARD). All of the members perform a pivotal role in signalling events that regulate apoptosis. Protein-protein interactions are mediated by self-self associations, in which CARD-CARD, DD-DD and DED-DED contacts are formed exclusively The three families possess remarkably similar structures, each comprising an antiparallel six helical bundle in the Greek Key topology. Structurally, the DD and CARD families are the most dissimilar. The former is comprised of two perpendicular three-helix bundles, whereas the latter CARD domain contains six helices that are almost parallel with each other. Interestingly, the interactions in CARD or DD containing heterodimers are quite different .
The clan contains the following 6 members:CARD CARD_2 Death Death_2 DED PYRIN
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 (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
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 UniProtKB sequence database using the family HMM
- 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:
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
- an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
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.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
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.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
If you find these logos useful in your own work, please consider citing the following article:
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.
|Author:||Ponting C, Schultz J, Bork P|
|Number in seed:||49|
|Number in full:||1705|
|Average length of the domain:||84.30 aa|
|Average identity of full alignment:||21 %|
|Average coverage of the sequence by the domain:||14.12 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 11927849 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||18|
|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
This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
There are 7 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 CARD domain has been found. There are 66 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...