CARD domain

Caspase recruitment domain

Structure of the RAIDD CARD.[1]
Identifiers
Symbol CARD
Pfam PF00619
InterPro IPR001315
SMART SM00114
PROSITE PS50209
SCOP 3crd
SUPERFAMILY 3crd
CDD cd01671

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.

CARD domains 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.

CARD domains 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).

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. 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

This list is incomplete; you can help by expanding it.

References

  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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