NKG2D Activating Receptor
Information on receptor ligand systems used by NK cells to specifically detect transformed cells has been accumulating rapidly. Killer cell lectin-like receptor subfamily K, member 1, also known as KLRK1, is the product of human gene. The KLRK1 has been d
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Rajesh K. Gupta and G.S. Gupta
31.1
NKG2D Activating Receptor (CD314, Synonyms KLRK1)
Information on receptor ligand systems used by NK cells to specifically detect transformed cells has been accumulating rapidly. Killer cell lectin-like receptor subfamily K, member 1, also known as KLRK1, is the product of human gene. The KLRK1 has been designated as CD314 and contains a C-type lectin-like domain (CTLD). KLRK1 is also known as: KLR; NKG2D; NKG2-D; FLJ17759; FLJ75772; D12S2489E. Human NKG2D was originally identified in 1991 as an orphan receptor on NK cells (Houchins et al. 1991). Although genetically mapping near the C-type lectin receptors CD94 and NKG2A-E, the NKG2D activating NK cell receptor has little sequence homology with these receptors and is expressed as a homodimer that signals through DAP10 rather than CD94 (Chap. 30). NKG2D binds to two distinct families of ligands, the MHC class I chain-related peptides (MICA and MICB) and the UL-16 binding proteins (ULBP). These ligands are upregulated in cells that have undergone neoplastic transformation, and NK cytotoxicity on tumor cells correlates with tumor expression of MICA and ULBP. The NKG2D differs from other members of the NKG2 family in significant ways. They do not form heterodimers with CD94 on the cell surface. Instead, they are expressed as homodimers, and each homodimer associates noncovalently with a homodimer of the adaptor protein DAP-10. The cytoplasmic tail of DAP-10 carries a YxxM motif, which can recruit the regulatory subunit p85 of phosphatidylinositol-3 kinase and Grb2 (see also Chap. 30). The NKG2D (KLRK1) is also widely expressed on T cells and other immune system cells, providing stimulatory or co-stimulatory signals. NKG2D drives target cell killing following engagement of diverse, conditionally expressed MHC class I-like protein ligands whose expression can signal cellular distress due to infection or transformation. The NKG2D ligand-binding site recognition is
highly degenerate that demonstrates its ability to simultaneously accommodate multiple non-conservative allelic or isoform substitutions in the ligands. The NKG2D degeneracy is achieved using distinct interaction mechanisms at each rigid interface: recognition degeneracy by “rigid adaptation.” While forming similar complexes with their ligand (HLA-E), other NKG2x NKR family members do not require such recognition degeneracy. However, NK cells are known to efficiently kill target cells that do not express HLA class I molecules, thus implying the existence of triggering receptors for non-HLA ligands (Zhang et al. 2005).
31.2
Characteristics of NKG2D
31.2.1 The Protein NKG2D is encoded by the KLRK1 (killer cell lectin-like receptor subfamily member 1) gene. NKG2D is a type II homodimeric transmembrane protein with an extracellular C-type (i.e. Ca2+-binding) lectin-like domain. The NKG2D gene exists within the “NK complex” on human chromosome 12 and mouse chromosome 6 (Ho et al. 1998). The physical location of the Cd94 (centromeric) and Nkg2d (telomeric) genes were mapp
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