(Taken from a review on the NKC published in Nature Reviews Immunology See review for appropriate citations.)
What is the NKC?
Where in the
genome is the NKC located?
What
are the general features of NKC-encoded receptors?
How
far back in evolution are NKC-related molecules conserved?
What
are the functions of NKC-encoded receptors?
How is inhibition
mediated?
What
characterizes the activation receptors?
What
characterizes the co-stimulatory receptor?
The NKC is a genomic region encoding structurally related receptors, first found on natural killer (NK) cells.
Where in the genome is the NKC located?
The mouse NKC is on distal mouse chromosome 6. The rat NKC is on chromosome 4, and the human NKC is on chromosome 12p13.
What are the general features of NKC-encoded receptors?
They are type II integral membrane proteins with external domains resembling C-type (Ca++-dependent) lectins. In general they are expressed as disulfide-linked dimers, either as homodimers or heterodimers. However, the NKC receptors generally lack the residues for coordinate binding of Ca++, indicating that they do not bind carbohydrates in the same manner as authentic C-type lectins.
How far back in evolution are NKC-related molecules conserved?
Molecules most related to NKC-encoded receptors have been described in the sea squirt and genomes of several poxviruses.
What are the functions of NKC-encoded receptors?
Initially some of the receptors were described as MHC class I-specific, inhibitory receptors on NK cells while others had activation function. Co-stimulatory function has more recently been described.
The inhibitory receptors contain the immuno-receptor tyrosine-based inhibitory motif (ITIM) in their cytoplasmic domains. When tyrosine phosphorylated, the ITIMs can recruit and activate phosphatases, such as SHP-1, a cytoplasmic tyrosine phosphatase, or SHIP, a inositol phosphatase.
What characterizes the activation receptors?
The activation receptors lack ITIMs and frequently contain a charged cytoplasmic residue that facilitates association with transmembrane signaling chains, such as DAP12 (DNAX activating protein of 12 kd, also known as KARAP, killer activation receptor associated protein) that contains immunoreceptor tyrosine-based activation motifs (ITAMs). Such signaling chains are required for optimal expression of the receptor and signal transduction in a manner analogous to the antigen signaling complexes of T and B cells.
What characterizes the co-stimulatory receptor?
One isoform of the NKC-encoded receptor, NKG2D, preferentially associates with DAP10, that does not contain an ITAM. Instead, it contains a motif (YxxM), for recruitment of phosphotidylinositol 3-kinase, an enzyme also implicated in co-stimulation of CD28.