NKp46

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NKp46

Existing structural data : 1oll , 1p6f

Properties of human protein
Mass / length primary structure 283 amino acids
Secondary to quaternary structure Type 1 transmembrane protein
Isoforms 5
Identifier
Gene names NCR1  ; CD335
External IDs
Occurrence
Homology family NCR1
Parent taxon Higher mammals

NKp46 ( gene : NCR1 ) is a receptor protein that is located in the cell membrane of natural killer cells (NK cells) in all higher mammals . NKp46 contributes to the ability of the killer cells to distinguish friend from enemy (cell) and accordingly to slow down or ramp up the activity of the killer cell.

physiology

With this receptor, NK cells recognize various target cells, are activated and destroy these target cells. This eliminates tumor cells and cells infected with bacteria or viruses.

Molecular structure

Structurally, the protein consists of two C2-type immunoglobulin- like domains with a structurally variable connector, a transmembrane region with characteristic positively and negatively charged amino acids and a small intracellular domain. There are three glycosylation sites.

Target structures

These are iW not known, are discussed heparan sulfate - proteoglycans of the cell surface and extracellular accessible vimentin , but not structurally characterized certainly ubiquitously occurring zellmembranexprimierte targets. In addition, viral molecules that recognize neuraminic acid, for example influenza hemagglutinins and sialidases , are bound via glycosylation .

Cells expressing target structures

Tumor cells (for example myeloma cells) and cells infected with intracellular pathogens (for example mycobacteria / tuberculosis, salmonella, trypanosomes) and some viruses (for example influenza, Sendai, vaccinia) are detected.

Signal transduction

With the transmembrane region, NKp46 binds (via salt bridges) to two molecules, the CD3ζ and the so-called Fcγ receptor ; Both have a so-called ITAM motif intracellularly , which leads to the activation of the small tyrosine kinase syk .

Expressing cells

Almost exclusively NK cells, in all stages of differentiation. An atypical T-ALL cell line (NKT-like / NT-like), which is being tested in clinical studies, is described.

Functional defects

We see a reduced membrane expression of the three NCRs in chronic hepatitis C and chronic HIV infection .

Individual evidence

  1. ↑ UniProt O76036
  2. ↑ Moretta L. et al. (2004): Unraveling natural killer cell function: triggering and inhibitory human NK receptors. In: EMBO J . 23 (2): 255-259. PMID 14685277
  3. ↑ Biassoni R. et al. (2003): Human natural killer cell receptors: insights into their molecular function and structure. In: J. Cell. Mol. Med. 7 (4): 376-387. PMID 14754506
  4. ↑ a b Pessino A. et al., Molecular cloning of NKp46: a novel member of the immunoglobulin superfamily involved in triggering of natural cytotoxicity. J Exp Med 188 (5): 953-60 (1998) PMID 9730896
  5. ^ Foster CE. et al., Crystal structure of the human natural killer (NK) cell activating receptor NKp46 reveals structural relationship to other leukocyte receptor complex immunoreceptors. J Biol Chem 278 (46): 46081-6 (2003) PMID 12960161
  6. ↑ Bloushtain N. et al. (2004): Membrane-associated heparan sulfate proteoglycans are involved in the recognition of cellular targets by NKp30 and NKp46. In: J. Immunol. 173 (4): 2392-2401. (2004) PMID 15294952
  7. ↑ a b Garg, A. et al. (2006): Vimentin expressed on Mycobacterium tuberculosis-infected human monocytes is involved in binding to the NKp46 receptor. In: J. Immunol. 177 (9): 6192-6198. PMID 17056548
  8. ↑ El-Sherbiny, YM. et al. (2007): The requirement for DNAM-1, NKG2D, and NKp46 in the natural killer cell-mediated killing of myeloma cells. In: Cancer Res. 67 (18): 8444-8449. PMID 17875681
  9. ↑ Vankayalapati, R. et al. (2002): The NKp46 receptor contributes to NK cell lysis of mononuclear phagocytes infected with an intracellular bacterium. In: J. Immunol. 168 (7): 3451-3457. PMID 11907104
  10. ↑ Vankayalapati, R. et al. (2006): Role of NK cell-activating receptors and their ligands in the lysis of mononuclear phagocytes infected with an intracellular bacterium. In: J. Immunol. 175 (7): 4611-4617. PMID 16177106
  11. ↑ Draghi M. et al. (2007): NKp46 and NKG2D recognition of infected dendritic cells is necessary for NK cell activation in the human response to influenza infection. In: J. Immunol. 178 (5): 2688-2698. PMID 17312110
  12. ↑ Markel, G. et al. (2004): The mechanisms controlling NK cell autoreactivity in TAP2-deficient patients. In: Blood . 103 (5): 1770-1778. PMID 14604968
  13. ↑ Chisholm, SE et al. (2006): Recognition of vaccinia virus-infected cells by human natural killer cells depends on natural cytotoxicity receptors. In: J. Virol. 80 (5): 2225-2233. PMID 16474130
  14. ^ Westgaard IH. et al., Rat NKp46 activates natural killer cell cytotoxicity and is associated with FcepsilonRIgamma and CD3zeta. J Leukoc Biol 76 (6): 1200-6 (2004) PMID 15356098
  15. ↑ Sivori S. et al., P46, a novel natural killer cell-specific surface molecule that mediates cell activation. J Exp Med 186 (7): 1129-36 (1997) PMID 9314561
  16. ↑ Brando C. et al., Receptors and lytic mediators regulating anti-tumor activity by the leukemic killer T cell line TALL-104. J Leukoc Biol 78 (2): 359-71 (2005) PMID 15937142
  17. ↑ Nattermann J. et al., Surface expression and cytolytic function of natural killer cell receptors is altered in chronic hepatitis C. Gut 55 (6): 869-77 (2006) PMID 16322112
  18. ↑ De Maria A. et al., The impaired NK cell cytolytic function in viremic HIV-1 infection is associated with a reduced surface expression of natural cytotoxicity receptors (NKp46, NKp30 and NKp44). Eur J Immunol 33 (9): 2410-8 (2003) PMID 12938217