NLR family CARD domain-containing protein 4 is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''NLRC4''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
Structure
The NLRC4 protein is highly conserved across mammalian species. It bears homology to the
''C. elegans'' Ced4 protein. It contains an N-terminal
CARD
Card or The Card may refer to:
Common uses
* Plastic cards of various types:
**Bank card
**Credit card
**Debit card
**Payment card
* Playing card, used in games
* Printed circuit board, or card
* Greeting card, given on special occasions
Arts an ...
domain, a central nucleotide binding/
NACHT domain, and a C-terminal leucine rich repeat (
LRR) domain. It belongs to a family of NLR proteins that includes the transcriptional co-activator
CIITA
CIITA is a human gene which encodes a protein called the class II, major histocompatibility complex, transactivator. Mutations in this gene are responsible for the bare lymphocyte syndrome in which the immune system is severely compromised and c ...
and the canonical inflammasome protein
NLRP3. A truncated murine NLRC4 was the first member of this family whose crystal structure was solved.
Function
NLRC4 is best associated with triggering formation of the
inflammasome. Unlike NLRP3, certain inflammasome-dependent functions of NLRC4 may be carried out independently of the inflammasome scaffold
ASC. Human Ced4 homologs include
APAF1,
NOD1 (CARD4), and
NOD2 (CARD15). These proteins have at least 1
N-terminal CARD domain followed by a centrally located nucleotide-binding domain (NBD or NACHT) and a
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...
regulatory domain, found only in mammals, that contains either
WD40 repeat
The WD40 repeat (also known as the WD or beta-transducin repeat) is a short structural motif of approximately 40 amino acids, often terminating in a tryptophan-aspartic acid (W-D) dipeptide. Tandem copies of these repeats typically fold togethe ...
s or
leucine-rich repeat
A leucine-rich repeat (LRR) is a protein structural motif that forms an α/β horseshoe tertiary structure, fold. It is composed of repeating 20–30 amino acid stretches that are unusually rich in the hydrophobic amino acid leucine. These Pr ...
s (LRRs). CARD12 is a member of the Ced4 family and can induce
apoptosis
Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
.
Interactions
NLRC4 has been shown to
interact with NAIP (there is one human NAIP but mice express at least 4 distinct NAIP proteins). The NAIP/NLRC4 interaction may determine the ligand specificity. NLRC4-dependent inflammasome activity activates
CASP1.
Under certain circumstances, NLRC4 and NLRP3 may occupy the same inflammasome complex.
Clinical significance
Humans bearing activating mutations in NLRC4 can develop an
autoinflammatory syndrome characterized by acute fever, hepatitis, very high serum ferritin, and other features suggestive of
Macrophage Activation Syndrome (MAS). Some patients also developed a potentially life-threatening enterocolitis that abated during early childhood.
In these patients, chronic and extraordinary elevation of serum
IL-18 is found, in distinction from patients with NLRP3 mutations who develop
Cryopyrin Associated Periodic Syndromes.
A large Japanese family had much milder disease associated with cold-induced urticaria that was caused by a dominantly inherited NLRC4 mutation.
References
Further reading
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LRR proteins
NOD-like receptors
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