Summary: Atypical caspase recruitment domain
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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 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.
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) 
- Ced-3 analog of caspase 9 in Caenorhabditis elegans
- AIRE Autoimmune Regulator 
- 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 . PMID 12101092.
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Atypical caspase recruitment domain Provide feedback
The N-terminal effector domain found in NLRC5. It adopts a six alpha-helix bundle with a general death fold. Structure and sequence analysis of the NLRC5-N indicate that it possesses a fold similar to the one of the death-fold domains; however, it displays significant differences in the number of core alpha-helices and their relative orientation. Hence, it is suggested that NLRC5 belongs to the caspase recruitment domain (CARD) subfamily as an atypical CARD .
Gutte PG, Jurt S, Grutter MG, Zerbe O;, Biochemistry. 2014;53:3106-3117.: Unusual structural features revealed by the solution NMR structure of the NLRC5 caspase recruitment domain. PUBMED:24815518 EPMC:24815518
This tab holds annotation information from the InterPro database.
No InterPro data for this Pfam family.
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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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 7 members:Atypical_Card CARD CARD_2 Death Death_2 DED PYRIN
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|Number in seed:||20|
|Number in full:||94|
|Average length of the domain:||94.50 aa|
|Average identity of full alignment:||51 %|
|Average coverage of the sequence by the domain:||5.58 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||1|
|Download:||download the raw HMM for this family|
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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 Atypical_Card domain has been found. There are 1 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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