Caspase recruitment domain-containing protein 11 also known asCARD-containing MAGUK protein 1 (Carma 1) is aprotein in theCARD-CC protein family that in humans is encoded by theCARD11gene.[5][6][7] CARD 11 is a membrane associated protein that is found in various human tissues, including the thymus, spleen, liver, and peripheral blood leukocytes. Similarly, CARD 11 is also found in abundance in various lines of cancer cells.[5]
The protein encoded by this gene belongs to themembrane-associated guanylate kinase (MAGUK) family, a class of proteins that functions as molecular scaffolds for the assembly of multiprotein complexes at specialized regions of the plasma membrane. This protein is also a member of the CARD protein family, which is defined by carrying a characteristic caspase-associated recruitment domain (CARD). CARD11 (CARMA1) has a domain structure similar to that ofCARD10 (CARMA3) andCARD14 (CARMA2) as a member of theCARD-CC family with a C terminal MAGUK domain (the so-called CARMA proteins). The CARD domain of proteins in theCARD-CC family have been shown to specifically interact withBCL10, a protein known to function as a positive regulator ofNF-κB activation by recruitment and activation ofMALT1. When overexpressed in cells, this protein family activates NF-κB and induces thephosphorylation of BCL10.[7]
CARD11 is critical forT cell andB cell function and is activated afterT cell receptor orB cell receptor stimulation. After receptor stimulation, CARD11 is phosphorylated byPKC-θ (in T cells) orPKC-β (in B cells). The phosphorylation induces formation of filamentous CARD11 multimers that recruitBCL10 andMALT1, which in turn activatesNF-κB. Loss of function mutations in CARD11 causesevere combined immunodeficiency (SCID) since the function of cells critical foradaptive immunity are disrupted.
This is the predicted structure of CARD11 produced by AlphaFold. The different colored regions reflect the confidence that a particular residue is in that location, with dark blue being the most confident and orange indicating the least confidence.
The structure of CARD11 involves multiple domains that impact the protein's ability to activateBCL10 andNF-κB activity. CARD11 has a CARD domain, a serine-threonine rich region, is associated with the N-terminus, which is essential forNF-κB signaling activity. The region following the CARD domain is highly coiled. In deleting the CARD domain, allNF-κB signaling activity was prevented. The CARD domain on CARD11 interacts with the CARD domain onBCL10 to initiate the signaling pathway.[5]
On the C-terminus of CARD11 there is the MAGUK domain that is associated with the cell membrane. This domain is often referred to as the inhibitory domain.Protein kinase C activates CARD11 by phosphorylating serine residues within the inhibitory domain.[5][8]
CARD11 has been shown tointeract withBCL10.[9] This interaction occurs between the CARD domain onBCL10 and the CARD domain on CARD11, and results in signal propagation and NF-κB activation.[8]
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Wang D, You Y, Case SM, McAllister-Lucas LM, Wang L, DiStefano PS, Nuñez G, Bertin J, Lin X (2002). "A requirement for CARMA1 in TCR-induced NF-kappa B activation".Nat. Immunol.3 (9):830–5.doi:10.1038/ni824.PMID12154356.S2CID19250072.
