CARD Domain
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Caspase recruitment domains, or caspase activation and recruitment domains (CARDs), are interaction motifs found in a wide array of
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s, typically those involved in processes relating to
inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
and
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
. 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 The death fold is a tertiary structure motif commonly found in proteins involved in apoptosis or inflammation-related processes. This motif is commonly found in domains that participate in protein–protein interactions leading to the format ...
, 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 A pyrin domain (PYD, also known as PAAD/DAPIN) is a protein domain and a subclass of protein motif known as the death fold, the 4th and most recently discovered member of the death domain superfamily (DDF). It was originally discovered in the p ...
(PYD),
death domain Death is the irreversible cessation of all biological functions that sustain an organism. For organisms with a brain, death can also be defined as the irreversible cessation of functioning of the whole brain, including brainstem, and brain ...
(DD), and
death effector domain The death-effector domain (DED) is a protein interaction domain found only in eukaryotes that regulates a variety of cellular signalling pathways. The DED domain is found in inactive procaspases (cysteine proteases) and proteins that regulate cas ...
(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. 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
caspase Caspases (cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-directed proteases) are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cystei ...
s 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 receptor Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are Bitopic protein, single-pass membrane-spanning Receptor (biochemistry), receptors usually expressed on sentinel cells such as macrophage ...
s. 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 Inflammasomes are cytosolic multiprotein oligomers of the innate immune system responsible for the activation of inflammatory responses. Activation and assembly of the inflammasome promotes proteolytic cleavage, maturation and secretion of pro-in ...
. 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 Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
, a common constituent of a number of viral genomes, including the para- and orthomyxoviridae and rhabdoviridae. Unlike NLRs, these proteins, termed
RIG-I RIG-I (retinoic acid-inducible gene I) is a cytosolic pattern recognition receptor (PRR) responsible for the type-1 interferon (IFN1) response. RIG-I is an essential molecule in the innate immune system for recognizing cells that have been infect ...
and
MDA5 MDA5 (melanoma differentiation-associated protein 5) is a RIG-I-like receptor dsRNA helicase enzyme that is encoded by the ''IFIH1'' gene in humans. MDA5 is part of the RIG-I-like receptor (RLR) family, which also includes RIG-I and LGP2, and ...
, contain twin N-terminal CARD domains and C-terminal
RNA helicase Helicases are a class of enzymes thought to be vital to all organisms. Their main function is to unpack an organism's genetic material. Helicases are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separati ...
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 Visa most commonly refers to: *Visa Inc., a US multinational financial and payment cards company ** Visa Debit card issued by the above company ** Visa Electron, a debit card ** Visa Plus, an interbank network *Travel visa, a document that allows ...
/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 inhibitor of nuclear factor kappa-B kinase (IKK)-protein-kinase family members. Although the canonical IKK family members
IKKa Inhibitor of nuclear factor kappa-B kinase subunit alpha (IKK-α) also known as IKK1 or conserved helix-loop-helix ubiquitous kinase (CHUK) is a protein kinase that in humans is encoded by the ''CHUK'' gene. IKK-α is part of the IκB kinase c ...
and IKKb are essential for virus-triggered
NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
activation, the noncanonical IKK family members TBK1 and
IKBKE Inhibitor of nuclear factor kappa-B kinase subunit epsilon also known as I-kappa-B kinase epsilon or IKK-epsilon is an enzyme that in humans is encoded by the ''IKBKE'' gene. Interactions IKBKE has been shown to interact with TANK. Function ...
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

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 Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea (which may be bloody if inflammation is severe), fever, abdominal distension ...
. Activating mutations in at least two related PYD-containing proteins,
cryopyrin NLR family pyrin domain containing 3 (NLRP3) (previously known as NACHT, LRR and PYD domains-containing protein 3 ALP3and cryopyrin), is a protein that in humans is encoded by the ''NLRP3'' gene located on the long arm of chromosome 1. NLRP3 is ...
/ CIAS-1 and pyrin/MEFV, have been linked to
Muckle–Wells syndrome Muckle–Wells syndrome (MWS) is a rare autosomal dominant disease which causes sensorineural deafness and recurrent hives, and can lead to amyloidosis. Individuals with MWS often have episodic fever, chills, and joint pain. As a result, MWS is ...
and
familial Mediterranean fever Familial Mediterranean fever (FMF) is a hereditary inflammatory disorder. FMF is an autoinflammatory disease caused by mutations in Mediterranean fever gene, which encodes a 781–amino acid protein called pyrin. While all ethnic groups are sus ...
, respectively.


List of CARD containing proteins

*
BIRC2 Baculoviral IAP repeat-containing protein 2 (also known as cIAP1) is a protein that in humans is encoded by the ''BIRC2'' gene. Function cIAP1 is a member of the Inhibitor of Apoptosis family that inhibit apoptosis by interfering with the acti ...
baculoviral
Inhibitor of apoptosis Inhibitors of apoptosis are a group of proteins that mainly act on the intrinsic pathway that block programmed cell death, which can frequently lead to cancer or other effects for the cell if mutated or improperly regulated. Many of these inhibit ...
(IAP) repeat-containing 2, also known as C-IAP

*
BIRC3 Baculoviral IAP repeat-containing protein3 (also known as cIAP2) is a protein that in humans is encoded by the ''BIRC3'' gene. cIAP2 is a member of the inhibitor of apoptosis family that inhibit apoptosis by interfering with the activation of ca ...
baculoviral IAP repeat-containing 3, also known as C-IAP

*
Caspase 1 Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosis ...
: caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase; ICE

*
Caspase 2 Caspase 2 also known as CASP2 is an enzyme that, in humans, is encoded by the ''CASP2'' gene. ''CASP2'' orthologs have been identified in nearly all mammals for which complete genome data are available. Unique orthologs are also present in bird ...
: caspase 2, apoptosis-related cysteine peptidas

*
Caspase 4 Caspase 4 is an enzyme that proteolytically cleaves other proteins at an aspartic acid residue (LEVD-), and belongs to a family of cysteine proteases called caspases. The function of caspase 4 is not fully known, but it is believed to be an in ...
: caspase 4, apoptosis-related cysteine peptidas

*
Caspase 5 Caspase 5 is an enzyme that proteolytically cleaves other proteins at an aspartic acid residue, and belongs to a family of cysteine proteases called caspases. It is an inflammatory caspase, along with caspase 1, caspase 4 and the murine caspase ...
: caspase 5, apoptosis-related cysteine peptidas

* Caspase-9, Caspase 9: caspase 9, apoptosis-related cysteine peptidas

*
Caspase 12 Caspase 12 is a protein that in humans is encoded by the ''CASP12'' gene. The protein belongs to a family of enzymes called caspases which cleave their Substrate (biochemistry), substrates at C-terminal aspartic acid residues. It is closely rela ...
: caspase 12, apoptosis-related cysteine peptidas

* Caspase 13: caspase 13, apoptosis-related cysteine peptidas

*
ICEBERG An iceberg is a piece of freshwater ice more than 15 m long that has broken off a glacier or an ice shelf and is floating freely in open (salt) water. Smaller chunks of floating glacially-derived ice are called "growlers" or "bergy bits". The ...
: caspase 1 inhibitor iceber

* Pseudo-ICE:Caspase-1 dominant-negative inhibitor Pseudo-ICE, also known as
COP1 ''For the membrane coated vesicle used in transport, see here.'' Fagol Caspase recruitment domain-containing protein 16 is an enzyme that in humans is encoded by the ''CARD16'' gene In biology, the word gene (from , ; "...Wilhelm Johannse ...
br>
* MDA-5: Melanoma differentiation-associated protein 5, also called ''Interferon-induced helicase C domain-containing protein 1'' (
IFIH1 MDA5 (melanoma differentiation-associated protein 5) is a RIG-I-like receptor dsRNA helicase enzyme that is encoded by the ''IFIH1'' gene in humans. MDA5 is part of the RIG-I-like receptor (RLR) family, which also includes RIG-I and LGP2, and f ...


* MAVS (gene), MAVS: Mitochondrial antiviral-signaling protein also known as ''CARD adapter inducing interferon-beta'' (Cardif/IPS-1

*
CRADD Death domain-containing protein CRADD is a protein that in humans is encoded by the ''CRADD'' gene. Function The protein encoded by this gene is a death domain (CARD/DD)-containing protein and has been shown to induce cell apoptosis. Through it ...
: Caspase and RIP adapter with death domain also known as ''RIP-associated protein with a death domain'' (RAIDD

* RAIDD-2: Death adaptor molecule RAIDD-

*
RIG-I RIG-I (retinoic acid-inducible gene I) is a cytosolic pattern recognition receptor (PRR) responsible for the type-1 interferon (IFN1) response. RIG-I is an essential molecule in the innate immune system for recognizing cells that have been infect ...
: Retinoic acid-inducible gene 1 protein, also known as ''DEAD-box protein 58'' ( DDX58

*
RIPK2 Receptor-interacting serine/threonine-protein kinase 2 is an enzyme that in humans is encoded by the ''RIPK2'' gene. This gene encodes a member of the receptor-interacting protein (RIP) family of serine/threonine protein kinases. The encoded prot ...
: receptor-interacting serine-threonine kinase 2 (also called cardiak, RIP2 or RICK kinase

*
BCL10 B-cell lymphoma/leukemia 10 is a protein that in humans is encoded by the ''BCL10'' gene. Like BCL2, BCL3, BCL5, BCL6, BCL7A, and BCL9, it has clinical significance in lymphoma. Function Bcl10 was identified by its translocation in a case of ...
: B-cell lymphoma/leukemia 10 protei

* BINCA: Bcl10-interacting CARD protein or BinCARD, also called chromosome 9 open reading frame 89 (C9orf89

* CARD6: caspase recruitment domain family, member

*
CARD8 Caspase recruitment domain-containing protein 8 is a protein that in humans is encoded by the ''CARD8'' gene. Function Caspase recruitment domain (CARD)-containing proteins, such as CARD8, are involved in pathways leading to activation of casp ...
/CARDINAL: caspase recruitment domain family, member

*
CARD9 Caspase recruitment domain-containing protein 9 is an adaptor protein of the CARD-CC protein family, which in humans is encoded by the ''CARD9'' gene. It mediates signals from pattern recognition receptors to activate pro-inflammatory and anti-i ...
: caspase recruitment domain family, member

*
CARD10 Caspase recruitment domain-containing protein 10 is a protein in the CARD-CC protein family that in humans is encoded by the ''CARD10'' gene. Function The caspase recruitment domain (CARD) is a protein module that consists of 6 or 7 antiparal ...
: caspase recruitment domain family, member 10 (also called CARMA3

*
CARD11 Caspase recruitment domain-containing protein 11 also known as CARD-containing MAGUK protein 1 (Carma 1) is a protein in the CARD-CC protein family that in humans is encoded by the ''CARD11'' gene. Function The protein encoded by this gene b ...
: caspase recruitment domain family, member 11 (also called CARMA1

*
CARD14 Caspase recruitment domain-containing protein 14, also known as D-containing MAGUK protein 2 (Carma 2), is a protein in the CARD-CC protein family that in humans is encoded by the ''CARD14'' gene. Function The protein encoded by this gene bel ...
: caspase recruitment domain family, member 14 (also called CARMA2

*
APAF1 Apoptotic protease activating factor 1, also known as APAF1, is a human homolog of ''C. elegans'' CED-4 gene. Function The protein was identified in the lab of Xiaodong Wang as an activator of caspase-3 in the presense of cytochromeC and dATP ...
: 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 NLR family CARD domain-containing protein 4 is a protein that in humans is encoded by the ''NLRC4'' gene. Structure The NLRC4 protein is highly conserved across mammalian species. It bears homology to the ''C. elegans'' Ced4 protein. It contai ...
)'', ''CARD, LRR, and NACHT-containing protein'' (CLAN) and Caspase recruitment domain-containing protein 12 (CARD12

*
NOD1 Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is a protein receptor that in humans is encoded by the ''NOD1'' gene. It recognizes bacterial molecules and stimulates an immune reaction . NOD1 protein contains a caspase recr ...
: nucleotide-binding oligomerization domain containing

*
NOD2 Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), also known as caspase recruitment domain-containing protein 15 (CARD15) or inflammatory bowel disease protein 1 (IBD1), is a protein that in humans is encoded by the ''NOD2'' g ...
: nucleotide-binding oligomerization domain containing

*
NLRC3 NLRC3, short for NOD-like receptor family CARD domain containing 3, is an intracellular protein that plays a role in the immune system. It was previously known as ''nucleotide-binding oligomerization domain, leucine rich repeat and CARD domain c ...
:
NOD-like receptor The nucleotide-binding oligomerization domain-like receptors, or NOD-like receptors (NLRs) (also known as nucleotide-binding leucine-rich repeat receptors), are intracellular sensors of pathogen-associated molecular patterns (PAMPs) that enter the ...
family CARD domain containing

*
NLRP1 NLRP1 encodes NACHT, LRR, FIIND, CARD domain and PYD domains-containing protein 1 in humans. NLRP1 was the first protein shown to form an inflammasome. Material was copied from this source, which is available under Creative Commons Attribution 4. ...
: NLR family, pyrin domain containing 1 (previously called NALP1

*
NOL3 Nucleolar protein 3 is a protein that in humans is encoded by the ''NOL3'' gene. Nol3 has been shown to be induced in multiple cancer types and acts as a repressor of apoptosis leading to resistance and proliferation. Paradoxically, loss of Nol3 ...
: nucleolar protein 3 (apoptosis repressor with CARD domain

*
PYCARD PYCARD, often referred to as ASC (Apoptosis-associated speck-like protein containing a CARD), is a protein that in humans is encoded by the ''PYCARD'' gene. It is localized mainly in the nucleus of monocytes and macrophages. In case of pathogen in ...
: PYD and CARD domain containing protein (also called ASC

* Ced-3 analog of caspase 9 in Caenorhabditis elegans *
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Autoimmune Regulato


References

* * * * * {{Protein domains Protein structure Protein domains Programmed cell death