CD94 KLRD1 (killer cell lectin-like receptor, subfamily D, member 1), Kp43
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 2 glycoprotein
NK Cell
T Cell
30 / 30

Expression
CD94 is expressed, in vitro, on most freshly-isolated NK cells but with a wide variation in the levels of expression.  It may not be detectable on a subset of fresh peripheral blood (PB) NK cells.  It is also present on subsets of gd and ab T cells.  NKG2 transcripts are expressed on NK cell lines and on some T cell clones and lines.  NKG2 proteins are expressed as disulfide-linked heterodimers with CD94 on the surface of NK cells and T cells. Different NK cell clones may express one or more NKG2 glycoproteins.  In mice, CD8+ cytotoxic T cells can upregulate CD94 expression thus reducing their cytotoxic activity.


Structure
MOLECULAR FAMILY NAME: Belongs to the C-type lectin superfamily.

CD94 is a single-pass type-2 180 aa glycoprotein.  It contains an 148 aa extracellular domain which contains a C-type lectin domain and 2 potential N-linked glycosylation sites, a 22 aa transmembrane domain and a 10 aa cytoplasmic tail with contains no known signaling motifs.  In NK/T cells, it covalently assembles with other C-type lectin molecules NKG2, corresponding to the kp43 and p39 subunits detected in SDS-PAGE.  CD94 is structurally related to several other molecules with C-type lectin domains such as CD23, CD69, CD72 and CD161 which are encoded within the NK gene complex, human chromosome 12, mouse chromosome 6.  They all contribute to NK cell function.  CD94 forms a disulfide-linked heterodimer with 2 members of the C-type lectin superfamily, NKG2A (43 kDa subunit) and NKG2C (39 kDa).  NKG2 was originally identified as 6 closely related cDNAs, NKG2-A, NKG2-B, NKG2-C, NKG2-D, NKG2-E and NKG2-F.  NKG2-A and -B are alternatively spliced transcripts of the same gene. NKG2 genes encode type 2 integral membrane proteins with an extracellular C-type lectin domains.  Molecules of the NKG2 family are structurally related to several other molecules such as Ly-49 family, NKR-P1 family, CD69 and CD94 and are encoded within the mouse and/or human NK gene complexes which contribute to NK cell function (See Ly-49).  NKG2 proteins are disulfide-bonded to CD94 proteins and are expressed as heterodimers on the surface of NK cells and some T cells.  Transfection studies suggest that NKG2 glycoproteins may also be expressed as disulfide-linked homodimers.  The cytoplasmic domain of NKG2A/B has 2 (I/V)XYXXL motifs but these are absent from other NKG2 molecules.

MOLECULAR MASS
Cell Type Unreduced Reduced
NK cells 70 kDa 30,43/39 kDa

The 30 kDa CD94 protein is poorly labeled with 125 I. The kp43 and p39 glycoproteins detected in SDS-PAGE correspond to other C-type lectins co-valently associated with CD94.

POST-TRANSCRIPTIONAL MODIFICATION

Alternatively splicing yields 3 different isoforms that differ in the presence or absence of the exon 2 sequence.

POST-TRANSLATIONAL MODIFICATION

CD94 has 2 potential N-linked glycosylation sites.

Ligands
CD94/NKG2 receptors have been implicated in the recognition of HLA-A, HLA-B and HLA-C, but there is currently no evidence for direct binding.  A soluble form of NKG2-C binds to an unidentified ligand on K562 cells and binding correlated with their susceptibility to NK cell lysis. NKG2 has been shown to associate with the cytoplasmic tyrosine phosphatase SHP-1, presumably through its cytoplasmic (I/V)XYXXL motifs.

LIGANDS AND MOLECULES ASSOCIATED WITH CD94
Molecule Comment
NKG2-A (kp43) 43 kD C-type lectin associated co-valently with CD94
p39 39 kD C-type lectin associated co-valently with CD94

In NK/T cells CD94 co-valently assembles with other C-type lectin molecules (NKG2), corresponding to the kp43 and p39 subunits detected in SDS-PAGE.





Function
CD94/NKG2 receptors play a role in recognition of MHC class I molecules by NK cells and some cytotoxic T cells. The ligation of CD94 on NK cells inhibits killing of target cells which express suitable MHC class I molecule ligands. However, CD94 ligation appears to activate some NK cells, suggesting that there may be stimulatory and inhibitory forms of CD94, probably due to the association of CD94 with different NKG2 subunits (NKG2A, C and E) to form receptors for HLA class I molecules.  CD94/NKG2A functions as an inhibitor receptor and has been implicated in activation or inhibition of NK cell functions like cytotoxicity and cytokine secretion.  Cross-linking of CD94/NKG2 dimers by HLA-E bearing taget cells results in the phosphorylation of two ITIMs present in the cytoplasmic domain of NKG2A but NKG2C and NKG2E lack ITIM motifs.  The binding of Src homology 2 domain-bearing tyrosine phosphatases SHP-1 and SHP-2 to the phosphorylated ITIMs leads to their activation and results in suppression of NK cytotoxicity.
Expression of CD94/NKG2A complexes on the cell surface of a large subset of NK cells appears to be constant via rapid recyling of internalized receptors, thus ensuring that interaction with ligand bearing normal cells does not result in an autoimmune response.  In contrast CD94/NKF2C and E complexes seem to be expressed at lower levels on the NK surface and act as activatory receptors.  Both NKG2C and E lack cytoplasmic signaling motifs but they associate with the signaling transducing protein DAP12.  CD94 antibodies modulate NK cell function triggering or inhibiting cytotoxicity and tumor necroisis factor production.
 
BIOCHEMICAL ACTIVITY

CD94, assembled with other C-type lectins (NKG2), functions as an inhibitory receptor specific for HLA class I molecules.

DISEASE RELEVANCE AND FUNCTION OF CD94 IN INTACT ANIMAL: No information.

Comments
MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD94: No information.

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD94: No information.

ADDITIONAL INSIGHTS

The p39 subunit is also a member of the NKG2 family. Co-expression of the CD94/NKG2 dimers will allow a precise study of their ligand interaction. No NKG2-specific mAbs were found in the 6th Workshop panel.  The Z199 mAb specifically identifies the CD94/NKG2-A and CD94/NKG2-B dimers.

Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 3824Q13241
NKG2L14542
NKG2PT0374P26718X54870
NKG2PT0374P26717X54860
NKG2PT0373P26716X54868
NKG2PT0372P26715X54867
Antibodies
HP-3D9   View Reactivity

Revised June 25, 2008


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