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33  structures 129  species 3  interactions 1660  sequences 127  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]
Identifiers
Symbol CARD
Pfam PF00619
InterPro IPR001315
SMART SM00114
PROSITE PS50209
SCOP 3crd
SUPERFAMILY 3crd

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[edit]

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[edit]

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.

CARD domains in the mammalian immune response[edit]

IL-1 and IL-18 processing[edit]

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[edit]

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 IKK3 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).

Autoimmunity[edit]

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[edit]

  • BIRC2 baculoviral Inhibitor of apoptosis (IAP) repeat-containing 2, also known as C-IAP1 [1]
  • BIRC3 baculoviral IAP repeat-containing 3, also known as C-IAP2 [2]
  • Caspase 1: caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase; ICE) [3]
  • Caspase 2: caspase 2, apoptosis-related cysteine peptidase [4]
  • Caspase 4: caspase 4, apoptosis-related cysteine peptidase [5]
  • Caspase 5: caspase 5, apoptosis-related cysteine peptidase [6]
  • Caspase 9: caspase 9, apoptosis-related cysteine peptidase [7]
  • Caspase 12: caspase 12, apoptosis-related cysteine peptidase [8]
  • Caspase 13: caspase 13, apoptosis-related cysteine peptidase [9]
  • ICEBERG: caspase 1 inhibitor iceberg [10]
  • Pseudo-ICE:Caspase-1 dominant-negative inhibitor Pseudo-ICE, also known as COP1 [11]
  • MDA-5: Melanoma differentiation-associated protein 5, also called Interferon-induced helicase C domain-containing protein 1 (IFIH1) [12]
  • MAVS: Mitochondrial antiviral-signaling protein also known as CARD adapter inducing interferon-beta (Cardif) [13]
  • CRADD: Caspase and RIP adapter with death domain also known as RIP-associated protein with a death domain (RAIDD) [14]
  • RAIDD-2: Death adaptor molecule RAIDD-2 [15]
  • RIG-I: Retinoic acid-inducible gene 1 protein, also known as DEAD-box protein 58 (DDX58) [16]
  • RIPK2: receptor-interacting serine-threonine kinase 2 (also called cardiak, RIP2 or RICK kinase) [17]
  • Bcl10: B-cell lymphoma/leukemia 10 protein [18]
  • BINCA: Bcl10-interacting CARD protein or BinCARD, also called chromosome 9 open reading frame 89 (C9orf89) [19]
  • CARD6: caspase recruitment domain family, member 6 [20]
  • CARD8/CARDINAL: caspase recruitment domain family, member 8 [21]
  • CARD9: caspase recruitment domain family, member 9 [22]
  • CARD10: caspase recruitment domain family, member 10 (also called CARMA3) [23]
  • CARD11: caspase recruitment domain family, member 11 (also called CARMA1) [24]
  • CARD14: caspase recruitment domain family, member 14 (also called CARMA2) [25]
  • APAF1: apoptotic peptidase activating factor 1 (also called CED4) [26]
  • GLAVA1: glavaris peptidase activating factor 1 (also called GLAV1) [27]
  • 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) [28]
  • NOD1: nucleotide-binding oligomerization domain containing 1 [29]
  • NOD2: nucleotide-binding oligomerization domain containing 2 [30]
  • NLRC3: NOD-like receptor family CARD domain containing 3 [31]
  • NLRP1: NLR family, pyrin domain containing 1 (previously called NALP1) [32]
  • NOL3: nucleolar protein 3 (apoptosis repressor with CARD domain) [33]
  • PYCARD: PYD and CARD domain containing protein (also called ASC) [34]
  • IPS1: RIG-I and MDA adaptor protein


References[edit]

  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


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR001315

The caspase recruitment domain domain (CARD) 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.

Gene Ontology

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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 5 members:

CARD Death Death_2 DED PYRIN

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.

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(60)
Full
(1660)
Representative proteomes NCBI
(1599)
Meta
(1)
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(218)
RP35
(269)
RP55
(437)
RP75
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  Seed
(60)
Full
(1660)
Representative proteomes NCBI
(1599)
Meta
(1)
RP15
(218)
RP35
(269)
RP55
(437)
RP75
(789)
Alignment:
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  Seed
(60)
Full
(1660)
Representative proteomes NCBI
(1599)
Meta
(1)
RP15
(218)
RP35
(269)
RP55
(437)
RP75
(789)
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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.

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.

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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
Author: Ponting C, Schultz J, Bork P
Number in seed: 60
Number in full: 1660
Average length of the domain: 84.60 aa
Average identity of full alignment: 21 %
Average coverage of the sequence by the domain: 14.74 %

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 23.9 23.9
Trusted cut-off 23.9 23.9
Noise cut-off 23.7 23.8
Model length: 85
Family (HMM) version: 16
Download: download the raw HMM for this family

Species distribution

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Interactions

There are 3 interactions for this family. More...

NB-ARC Bcl-2 CARD

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 CARD domain has been found. There are 33 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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