2l35

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Structure of the DAP12-NKG2C transmembrane heterotrimerStructure of the DAP12-NKG2C transmembrane heterotrimer

Structural highlights

2l35 is a 2 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Solution NMR, 15 models
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

TYOBP_HUMAN Nasu-Hakola disease. The disease is caused by mutations affecting the gene represented in this entry.

Function

TYOBP_HUMAN Non-covalently associates with activating receptors of the CD300 family. Cross-linking of CD300-TYROBP complexes results in cellular activation. Involved for instance in neutrophil activation mediated by integrin.NKG2C_HUMAN Immune activating receptor involved in self-nonself discrimination. In complex with KLRD1 on cytotoxic lymphocyte subsets, recognizes non-classical major histocompatibility (MHC) class Ib HLA-E loaded with signal sequence-derived peptides from non-classical MHC class Ib HLA-G molecules, likely playing a role in the generation and effector functions of adaptive natural killer (NK) cells and in maternal-fetal tolerance during pregnancy (PubMed:30134159, PubMed:37264229, PubMed:9754572). Regulates the effector functions of terminally differentiated cytotoxic lymphocyte subsets, and in particular may play a role in adaptive NK cell response to viral infection (PubMed:20952657, PubMed:21825173). Upon HLA-E-peptide binding, transmits intracellular signals via the adapter protein TYROBP/DAP12, triggering the phosphorylation of proximal signaling molecules and cell activation (PubMed:15940674, PubMed:9655483).[1] [2] [3] [4] [5] [6] [7]

Publication Abstract from PubMed

Many receptors that activate cells of the immune system are multisubunit membrane protein complexes in which ligand recognition and signaling functions are contributed by separate protein modules. Receptors and signaling subunits assemble through contacts among basic and acidic residues in their transmembrane domains to form the functional complexes. Here we report the nuclear magnetic resonance (NMR) structure of the membrane-embedded, heterotrimeric assembly formed by association of the DAP12 signaling module with the natural killer (NK) cell-activating receptor NKG2C. The main intramembrane contact site is formed by a complex electrostatic network involving five hydrophilic transmembrane residues. Functional mutagenesis demonstrated that similar polar intramembrane motifs are also important for assembly of the NK cell-activating NKG2D-DAP10 complex and the T cell antigen receptor (TCR)-invariant signaling protein CD3 complex. This structural motif therefore lies at the core of the molecular organization of many activating immunoreceptors.

The structural basis for intramembrane assembly of an activating immunoreceptor complex.,Call ME, Wucherpfennig KW, Chou JJ Nat Immunol. 2010 Nov;11(11):1023-9. Epub 2010 Oct 3. PMID:20890284[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Guma M, Busch LK, Salazar-Fontana LI, Bellosillo B, Morte C, Garcia P, Lopez-Botet M. The CD94/NKG2C killer lectin-like receptor constitutes an alternative activation pathway for a subset of CD8+ T cells. Eur J Immunol. 2005 Jul;35(7):2071-80. doi: 10.1002/eji.200425843. PMID:15940674 doi:http://dx.doi.org/10.1002/eji.200425843
  2. ↑ Angelini DF, Zambello R, Galandrini R, Diamantini A, Placido R, Micucci F, Poccia F, Semenzato G, Borsellino G, Santoni A, Battistini L. NKG2A inhibits NKG2C effector functions of gammadelta T cells: implications in health and disease. J Leukoc Biol. 2011 Jan;89(1):75-84. doi: 10.1189/jlb.0710413. Epub 2010 Oct 15. PMID:20952657 doi:http://dx.doi.org/10.1189/jlb.0710413
  3. ↑ Lopez-Verges S, Milush JM, Schwartz BS, Pando MJ, Jarjoura J, York VA, Houchins JP, Miller S, Kang SM, Norris PJ, Nixon DF, Lanier LL. Expansion of a unique CD57(+)NKG2Chi natural killer cell subset during acute human cytomegalovirus infection. Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):14725-32. doi: , 10.1073/pnas.1110900108. Epub 2011 Aug 8. PMID:21825173 doi:http://dx.doi.org/10.1073/pnas.1110900108
  4. ↑ Rolle A, Meyer M, Calderazzo S, Jager D, Momburg F. Distinct HLA-E Peptide Complexes Modify Antibody-Driven Effector Functions of Adaptive NK Cells. Cell Rep. 2018 Aug 21;24(8):1967-1976.e4. doi: 10.1016/j.celrep.2018.07.069. PMID:30134159 doi:http://dx.doi.org/10.1016/j.celrep.2018.07.069
  5. ↑ Lin Z, Bashirova AA, Viard M, Garner L, Quastel M, Beiersdorfer M, Kasprzak WK, Akdag M, Yuki Y, Ojeda P, Das S, Andresson T, Naranbhai V, Horowitz A, McMichael AJ, Hoelzemer A, Gillespie GM, Garcia-Beltran WF, Carrington M. HLA class I signal peptide polymorphism determines the level of CD94/NKG2-HLA-E-mediated regulation of effector cell responses. Nat Immunol. 2023 Jul;24(7):1087-1097. PMID:37264229 doi:10.1038/s41590-023-01523-z
  6. ↑ Lanier LL, Corliss B, Wu J, Phillips JH. Association of DAP12 with activating CD94/NKG2C NK cell receptors. Immunity. 1998 Jun;8(6):693-701. doi: 10.1016/s1074-7613(00)80574-9. PMID:9655483 doi:http://dx.doi.org/10.1016/s1074-7613(00)80574-9
  7. ↑ Llano M, Lee N, Navarro F, Garcia P, Albar JP, Geraghty DE, Lopez-Botet M. HLA-E-bound peptides influence recognition by inhibitory and triggering CD94/NKG2 receptors: preferential response to an HLA-G-derived nonamer. Eur J Immunol. 1998 Sep;28(9):2854-63. doi: , 10.1002/(SICI)1521-4141(199809)28:09<2854::AID-IMMU2854>3.0.CO;2-W. PMID:9754572 doi:<2854::AID-IMMU2854>3.0.CO;2-W http://dx.doi.org/10.1002/(SICI)1521-4141(199809)28:09<2854::AID-IMMU2854>3.0.CO;2-W
  8. ↑ Call ME, Wucherpfennig KW, Chou JJ. The structural basis for intramembrane assembly of an activating immunoreceptor complex. Nat Immunol. 2010 Nov;11(11):1023-9. Epub 2010 Oct 3. PMID:20890284 doi:10.1038/ni.1943
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