Schultz et al. (1998) Proc. Natl. Acad. Sci. USA 95, 5857-5864
Letunic et al. (2012) Nucleic Acids Res , doi:10.1093/nar/gkr931

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CARD Caspase recruitment domain

SMART accession number:	SM00114
Description:	Motif contained in proteins involved in apoptotic signalling. Mediates homodimerisation. Structure consists of six antiparallel helices arranged in a topology homologue to the DEATH and the DED domain.
Interpro abstract (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 IPR000488) and the death effector domain (DED, see IPR001875), 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 (IPR007111) (in Nal1 and Bir1), NB-ARC (IPR002182) (in Apaf-1), pyrin/dapin domains (IPR004020) (in Nal1), leucine-rich repeats (in Nal1), WD repeats (IPR001680) (in Apaf1), Src homology domains (IPR001452), PDZ (IPR001478), 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.
GO process:	regulation of apoptotic process (GO:0042981)
GO component:	intracellular (GO:0005622)
GO function:	protein binding (GO:0005515)
Family alignment:	View or CHROMA formatCLUSTALW formatMSF formatFASTA formatPIR format

There are 521 CARD domains in 492 proteins in SMART's nrdb database.

Click on the following links for more information.

• Evolution (species in which this domain is found)

• Click on to expand nodes. To display all proteins with a CARD domain in a specific node, click on it.

  This tree shows only several representative species. The complete taxonomic breakdown of all proteins with CARD domain is also avaliable.

  Useful shortcuts: Expand all nodes or Collapse tree
  Go to specific node: Caenorhabditis elegans, Homo sapiens, Mus musculus, Rattus norvegicus, Takifugu rubripes

• Cellular role (predicted cellular role)

• Binding / catalysis: protein binding, homodimerization

• Literature (relevant references for this domain)

• Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

  • Chou JJ, Matsuo H, Duan H, Wagner G
  • Solution structure of the RAIDD CARD and model for CARD/CARD interaction in caspase-2 and caspase-9 recruitment.
  • Cell. 1998; 94: 171-80
  • Display abstract

  • Apoptosis requires recruitment of caspases by receptor-associated adaptors through homophilic interactions between the CARDs (caspase recruitment domains) of adaptor proteins and prodomains of caspases. We have solved the CARD structure of the RAIDD adaptor protein that recruits ICH-1/caspase-2. It consists of six tightly packed helices arranged in a topology homologous to the Fas death domain. The surface contains a basic and an acidic patch on opposite sides. This polarity is conserved in the ICH-1 CARD as indicated by homology modeling. Mutagenesis data suggest that these patches mediate CARD/CARD interaction between RAIDD and ICH-1. Subsequent modeling of the CARDs of Apaf-1 and caspase-9, as well as Ced-4 and Ced-3, showed that the basic/acidic surface polarity is highly conserved, suggesting a general mode for CARD/CARD interaction.

  • Koseki T, Inohara N, Chen S, Nunez G
  • ARC, an inhibitor of apoptosis expressed in skeletal muscle and heart that interacts selectively with caspases.
  • Proc Natl Acad Sci U S A. 1998; 95: 5156-60
  • Display abstract

  • We have identified and characterized ARC, apoptosis repressor with caspase recruitment domain (CARD). Sequence analysis revealed that ARC contains an N-terminal CARD fused to a C-terminal region rich in proline/glutamic acid residues. The CARD domain of ARC exhibited significant homology to the prodomains of apical caspases and the CARDs present in the cell death regulators Apaf-1 and RAIDD. Immunoprecipitation analysis revealed that ARC interacts with caspase-2, -8, and Caenorhabditis elegans CED-3, but not with caspase-1, -3, or -9. ARC inhibited apoptosis induced by caspase-8 and CED-3 but not that mediated by caspase-9. Further analysis showed that the enzymatic activity of caspase-8 was inhibited by ARC in 293T cells. Consistent with the inhibition of caspase-8, ARC attenuated apoptosis induced by FADD and TRADD and that triggered by stimulation of death receptors coupled to caspase-8, including CD95/Fas, tumor necrosis factor-R1, and TRAMP/DR3. Remarkably, the expression of human ARC was primarily restricted to skeletal muscle and cardiac tissue. Thus, ARC represents an inhibitor of apoptosis expressed in muscle that appears to selectively target caspases. Delivery of ARC by gene transfer or enhancement of its endogenous activity may provide a strategy for the treatment of diseases that are characterized by inappropriately increased cell death in muscle tissue.

  • Hofmann K, Bucher P, Tschopp J
  • The CARD domain: a new apoptotic signalling motif.
  • Trends Biochem Sci. 1997; 22: 155-6

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

  • Interleukin-1 beta converting enzyme (ICE) is the first enzyme of a new family of cysteine endoproteinases to be isolated and characterized. An overview of the structure and activity of ICE is outlined together with highlights of salient features common to members of each of the family members.

• Metabolism (metabolic pathways involving proteins which contain this domain)

• % proteins involved KEGG pathway ID Description 16.91 map05222 Small cell lung cancer 16.91 map04210 Apoptosis 10.29 map04120 Ubiquitin mediated proteolysis 10.29 map04510 Focal adhesion 6.62 map04115 p53 signaling pathway 5.15 map05210 Colorectal cancer 5.15 map05213 Endometrial cancer 5.15 map04370 VEGF signaling pathway 5.15 map05212 Pancreatic cancer 5.15 map05223 Non-small cell lung cancer 5.15 map05215 Prostate cancer 3.68 map05040 Huntington's disease 3.68 map05050 Dentatorubropallidoluysian atrophy (DRPLA) 0.74 map05120 Epithelial cell signaling in Helicobacter pylori infection This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with CARD domain which could be assigned to a KEGG orthologous group, and not all proteins containing CARD domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

• Structure (3D structures containing this domain)

• 3D Structures of CARD domains in PDB

  PDB code	Main view	Title
  1dgn		Solution structure of iceberg, an inhibitor of interleukin- 1beta generation
  2a5y		Structure of a ced-4/ced-9 complex
  2b1w		Solution structure of the nod1 caspase activating and recruitment domain
  2dbd		Solution structure of the card domain in human caspase recruitment domain protein 4 (nod1 protein)
  2nsn		Crystal structure of caspace activation and recruitment domain (card) of nod1
  2nz7		Crystal structure analysis of caspase-recruitment domain (card) of nod1
  3crd		Nmr structure of the raidd card domain, 15 structures
  3ygs		Apaf-1 card in complex with prodomain of procaspase-9

• Links (links to other resources describing this domain)

• INTERPRO	IPR001315

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