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342  structures 441  species 0  interactions 11008  sequences 589  architectures

Family: CARD (PF00619)

Summary: Caspase recruitment domain

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CARD domain Edit Wikipedia article

Caspase recruitment domain
PDB 3crd EBI.jpg
Structure of the RAIDD CARD.[1]
Caspase recruitment domain, IPS1/RIG-I

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.

Basic features

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.

In apoptosis

CARD domains were originally characterized based on their involvement in the regulation of caspase activation and apoptosis.[2] 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.

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.

Antiviral signaling

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


  1. ^ 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.
  2. ^ 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.

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Caspase recruitment domain Provide feedback

Motif contained in proteins involved in apoptotic signaling. Predicted to possess a DEATH (PF00531) domain-like fold .

Literature references

  1. Hofmann K, Bucher P, Tschopp J; , Trends Biochem Sci 1997;22:155-156.: The CARD domain: a new apoptotic signalling motif. PUBMED:9175472 EPMC:9175472

  2. Miller DK, Myerson J, Becker JW; , J Cell Biochem 1997;64:2-10.: The interleukin-1 beta converting enzyme family of cysteine proteases. PUBMED:9015748 EPMC:9015748

Internal database links

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 , PUBMED:22065589 ]. 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.

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 Death (CL0041), which has the following description:

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 [1].

The clan contains the following 7 members:

Atypical_Card 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 and the UniProtKB 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.

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

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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...


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.

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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: SMART
Previous IDs: none
Type: Domain
Sequence Ontology: SO:0000417
Author: Ponting CP , Schultz J, Bork P
Number in seed: 47
Number in full: 11008
Average length of the domain: 83.90 aa
Average identity of full alignment: 20 %
Average coverage of the sequence by the domain: 13.19 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 23.9 23.9
Trusted cut-off 23.9 23.9
Noise cut-off 23.8 23.8
Model length: 85
Family (HMM) version: 24
Download: download the raw HMM for this family

Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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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 342 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 sequence.

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AlphaFold Structure Predictions

The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.

Protein Predicted structure External Information
A0A0G2JTL6 View 3D Structure Click here
A0A0G2K4Z7 View 3D Structure Click here
A0A0G2KV16 View 3D Structure Click here
A0A0G2QC28 View 3D Structure Click here
A0A0R4IJE4 View 3D Structure Click here
A0A0R4ISE6 View 3D Structure Click here
A0A0R4IX85 View 3D Structure Click here
A0A1D5NS76 View 3D Structure Click here
A0A288CG41 View 3D Structure Click here
A0A2R8Q4Z2 View 3D Structure Click here
A0A2R8Q8W9 View 3D Structure Click here
A0A2R8QP14 View 3D Structure Click here
A0A386CAB9 View 3D Structure Click here
A1Z198 View 3D Structure Click here
A2AIV8 View 3D Structure Click here
A2CE85 View 3D Structure Click here
B0S6V5 View 3D Structure Click here
B0V1H3 View 3D Structure Click here
B0V1H4 View 3D Structure Click here
D3ZB14 View 3D Structure Click here
D4A425 View 3D Structure Click here
D4ADT7 View 3D Structure Click here
E7EXQ0 View 3D Structure Click here
E7EZ76 View 3D Structure Click here
E7F7L0 View 3D Structure Click here
E7F8A6 View 3D Structure Click here
E9PSM0 View 3D Structure Click here
E9PWH2 View 3D Structure Click here
F1M649 View 3D Structure Click here
F1QPT8 View 3D Structure Click here
F1QSB1 View 3D Structure Click here
F7FLN8 View 3D Structure Click here
F8W3K2 View 3D Structure Click here
G3V783 View 3D Structure Click here
G3V8L1 View 3D Structure Click here
M0R6R8 View 3D Structure Click here
O08736 View 3D Structure Click here
O08863 View 3D Structure Click here
O14727 View 3D Structure Click here
O43353 View 3D Structure Click here