ID KLRD1_HUMAN Reviewed; 179 AA.
AC Q13241; O43321; O43773; Q9UBE3; Q9UEQ0;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 31-MAY-2011, sequence version 2.
DT 24-JAN-2024, entry version 196.
DE RecName: Full=Natural killer cells antigen CD94;
DE AltName: Full=KP43;
DE AltName: Full=Killer cell lectin-like receptor subfamily D member 1;
DE AltName: Full=NK cell receptor;
DE AltName: CD_antigen=CD94 {ECO:0000303|PubMed:18083576};
GN Name=KLRD1; Synonyms=CD94;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT ALA-25.
RC TISSUE=Blood;
RX PubMed=7589107; DOI=10.1002/eji.1830250904;
RA Chang C., Rodriguez A., Carretero M., Lopez-Botet M., Phillips J.H.,
RA Lanier L.L.;
RT "Molecular characterization of human CD94: a type II membrane glycoprotein
RT related to the C-type lectin superfamily.";
RL Eur. J. Immunol. 25:2433-2437(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ALA-25.
RC TISSUE=Placenta;
RX PubMed=9472066; DOI=10.1007/s002510050362;
RA Rodriguez A., Carretero M., Glienke J., Bellon T., Ramirez A., Lehrach H.,
RA Francis F., Lopez-Botet M.;
RT "Structure of the human CD94 C-type lectin gene.";
RL Immunogenetics 47:305-309(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE (ISOFORM 2).
RA Biassoni R.;
RL Submitted (JUN-1997) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 3).
RX PubMed=9601951; DOI=10.1007/s002510050407;
RA Furukawa H., Yabe T., Watanabe K., Miyamoto R., Akaza T., Tadokoro K.,
RA Tohma S., Inoue T., Yamamoto K., Juji T.;
RT "A alternatively spliced form of the human CD94 gene.";
RL Immunogenetics 48:87-88(1998).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C.,
RA Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R.,
RA Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E.,
RA Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y.,
RA Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G.,
RA Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H.,
RA Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S.,
RA Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M.,
RA Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H.,
RA Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q.,
RA Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V.,
RA Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E.,
RA Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R.,
RA David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E.,
RA D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N.,
RA Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N.,
RA Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R.,
RA Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S.,
RA LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H.,
RA Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P.,
RA Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G.,
RA Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E.,
RA Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S.,
RA Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O.,
RA Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y.,
RA Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A.,
RA Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F.,
RA Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L.,
RA Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G.,
RA Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT ALA-25.
RC TISSUE=Blood;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=9430220; DOI=10.1016/s1074-7613(00)80393-3;
RA Valiante N.M., Uhrberg M., Shilling H.G., Lienert-Weidenbach K.,
RA Arnett K.L., D'Andrea A., Phillips J.H., Lanier L.L., Parham P.;
RT "Functionally and structurally distinct NK cell receptor repertoires in the
RT peripheral blood of two human donors.";
RL Immunity 7:739-751(1997).
RN [8]
RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=9485206;
RX DOI=10.1002/(sici)1521-4141(199801)28:01<264::aid-immu264>3.0.co;2-o;
RA Le Drean E., Vely F., Olcese L., Cambiaggi A., Guia S., Krystal G.,
RA Gervois N., Moretta A., Jotereau F., Vivier E.;
RT "Inhibition of antigen-induced T cell response and antibody-induced NK cell
RT cytotoxicity by NKG2A: association of NKG2A with SHP-1 and SHP-2 protein-
RT tyrosine phosphatases.";
RL Eur. J. Immunol. 28:264-276(1998).
RN [9]
RP FUNCTION.
RX PubMed=9754572;
RX DOI=10.1002/(sici)1521-4141(199809)28:09<2854::aid-immu2854>3.0.co;2-w;
RA Llano M., Lee N., Navarro F., Garcia P., Albar J.P., Geraghty D.E.,
RA Lopez-Botet M.;
RT "HLA-E-bound peptides influence recognition by inhibitory and triggering
RT CD94/NKG2 receptors: preferential response to an HLA-G-derived nonamer.";
RL Eur. J. Immunol. 28:2854-2863(1998).
RN [10]
RP FUNCTION, AND INTERACTION WITH KLRC2 AND TYROBP.
RX PubMed=9655483; DOI=10.1016/s1074-7613(00)80574-9;
RA Lanier L.L., Corliss B., Wu J., Phillips J.H.;
RT "Association of DAP12 with activating CD94/NKG2C NK cell receptors.";
RL Immunity 8:693-701(1998).
RN [11]
RP FUNCTION, AND INTERACTION WITH HLA-E-PEPTIDE COMPLEX.
RX PubMed=9486650; DOI=10.1038/35869;
RA Braud V.M., Allan D.S., O'Callaghan C.A., Soederstroem K., D'Andrea A.,
RA Ogg G.S., Lazetic S., Young N.T., Bell J.I., Phillips J.H., Lanier L.L.,
RA McMichael A.J.;
RT "HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C.";
RL Nature 391:795-799(1998).
RN [12]
RP INTERACTION WITH HLA-E-PEPTIDE COMPLEX, AND SUBUNIT.
RX PubMed=10428963; DOI=10.1093/emboj/18.15.4250;
RA Vales-Gomez M., Reyburn H.T., Erskine R.A., Lopez-Botet M.,
RA Strominger J.L.;
RT "Kinetics and peptide dependency of the binding of the inhibitory NK
RT receptor CD94/NKG2-A and the activating receptor CD94/NKG2-C to HLA-E.";
RL EMBO J. 18:4250-4260(1999).
RN [13]
RP FUNCTION (MICROBIAL INFECTION).
RX PubMed=10669413; DOI=10.1126/science.287.5455.1031;
RA Tomasec P., Braud V.M., Rickards C., Powell M.B., McSharry B.P., Gadola S.,
RA Cerundolo V., Borysiewicz L.K., McMichael A.J., Wilkinson G.W.;
RT "Surface expression of HLA-E, an inhibitor of natural killer cells,
RT enhanced by human cytomegalovirus gpUL40.";
RL Science 287:1031-1031(2000).
RN [14]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=12387742; DOI=10.1016/s1074-7613(02)00427-2;
RA Jabri B., Selby J.M., Negulescu H., Lee L., Roberts A.I., Beavis A.,
RA Lopez-Botet M., Ebert E.C., Winchester R.J.;
RT "TCR specificity dictates CD94/NKG2A expression by human CTL.";
RL Immunity 17:487-499(2002).
RN [15]
RP FUNCTION.
RX PubMed=12165520; DOI=10.4049/jimmunol.169.4.1948;
RA Kabat J., Borrego F., Brooks A., Coligan J.E.;
RT "Role that each NKG2A immunoreceptor tyrosine-based inhibitory motif plays
RT in mediating the human CD94/NKG2A inhibitory signal.";
RL J. Immunol. 169:1948-1958(2002).
RN [16]
RP FUNCTION (MICROBIAL INFECTION).
RX PubMed=15751767; DOI=10.1177/135965350501000107;
RA Nattermann J., Nischalke H.D., Hofmeister V., Kupfer B., Ahlenstiel G.,
RA Feldmann G., Rockstroh J., Weiss E.H., Sauerbruch T., Spengler U.;
RT "HIV-1 infection leads to increased HLA-E expression resulting in impaired
RT function of natural killer cells.";
RL Antivir. Ther. 10:95-107(2005).
RN [17]
RP FUNCTION, AND INTERACTION WITH TYROBP.
RX PubMed=15940674; DOI=10.1002/eji.200425843;
RA Guma M., Busch L.K., Salazar-Fontana L.I., Bellosillo B., Morte C.,
RA Garcia P., Lopez-Botet M.;
RT "The CD94/NKG2C killer lectin-like receptor constitutes an alternative
RT activation pathway for a subset of CD8+ T cells.";
RL Eur. J. Immunol. 35:2071-2080(2005).
RN [18]
RP FUNCTION.
RX PubMed=18064301; DOI=10.1172/jci30989;
RA Bhagat G., Naiyer A.J., Shah J.G., Harper J., Jabri B., Wang T.C.,
RA Green P.H., Manavalan J.S.;
RT "Small intestinal CD8+TCRgammadelta+NKG2A+ intraepithelial lymphocytes have
RT attributes of regulatory cells in patients with celiac disease.";
RL J. Clin. Invest. 118:281-293(2008).
RN [19]
RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=20952657; DOI=10.1189/jlb.0710413;
RA Angelini D.F., Zambello R., Galandrini R., Diamantini A., Placido R.,
RA Micucci F., Poccia F., Semenzato G., Borsellino G., Santoni A.,
RA Battistini L.;
RT "NKG2A inhibits NKG2C effector functions of gammadelta T cells:
RT implications in health and disease.";
RL J. Leukoc. Biol. 89:75-84(2011).
RN [20]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=21825173; DOI=10.1073/pnas.1110900108;
RA Lopez-Verges S., Milush J.M., Schwartz B.S., Pando M.J., Jarjoura J.,
RA York V.A., Houchins J.P., Miller S., Kang S.M., Norris P.J., Nixon D.F.,
RA Lanier L.L.;
RT "Expansion of a unique CD57-positive NKG2Chi natural killer cell subset
RT during acute human cytomegalovirus infection.";
RL Proc. Natl. Acad. Sci. U.S.A. 108:14725-14732(2011).
RN [21]
RP FUNCTION (MICROBIAL INFECTION).
RX PubMed=23335510; DOI=10.1074/jbc.m112.409672;
RA Heatley S.L., Pietra G., Lin J., Widjaja J.M., Harpur C.M., Lester S.,
RA Rossjohn J., Szer J., Schwarer A., Bradstock K., Bardy P.G., Mingari M.C.,
RA Moretta L., Sullivan L.C., Brooks A.G.;
RT "Polymorphism in human cytomegalovirus UL40 impacts on recognition of human
RT leukocyte antigen-E (HLA-E) by natural killer cells.";
RL J. Biol. Chem. 288:8679-8690(2013).
RN [22]
RP FUNCTION.
RX PubMed=30503213; DOI=10.1016/j.cell.2018.10.014;
RA Andre P., Denis C., Soulas C., Bourbon-Caillet C., Lopez J., Arnoux T.,
RA Blery M., Bonnafous C., Gauthier L., Morel A., Rossi B., Remark R.,
RA Breso V., Bonnet E., Habif G., Guia S., Lalanne A.I., Hoffmann C.,
RA Lantz O., Fayette J., Boyer-Chammard A., Zerbib R., Dodion P.,
RA Ghadially H., Jure-Kunkel M., Morel Y., Herbst R., Narni-Mancinelli E.,
RA Cohen R.B., Vivier E.;
RT "Anti-NKG2A mAb Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity
RT by Unleashing Both T and NK Cells.";
RL Cell 175:1731-1743.e13(2018).
RN [23]
RP FUNCTION.
RX PubMed=30134159; DOI=10.1016/j.celrep.2018.07.069;
RA Roelle A., Meyer M., Calderazzo S., Jaeger D., Momburg F.;
RT "Distinct HLA-E Peptide Complexes Modify Antibody-Driven Effector Functions
RT of Adaptive NK Cells.";
RL Cell Rep. 24:1967-1976(2018).
RN [24]
RP FUNCTION.
RX PubMed=30860984; DOI=10.1172/jci123955;
RA Kamiya T., Seow S.V., Wong D., Robinson M., Campana D.;
RT "Blocking expression of inhibitory receptor NKG2A overcomes tumor
RT resistance to NK cells.";
RL J. Clin. Invest. 129:2094-2106(2019).
RN [25]
RP FUNCTION (MICROBIAL INFECTION).
RX PubMed=32859121; DOI=10.3390/cells9091975;
RA Bortolotti D., Gentili V., Rizzo S., Rotola A., Rizzo R.;
RT "SARS-CoV-2 Spike 1 Protein Controls Natural Killer Cell Activation via the
RT HLA-E/NKG2A Pathway.";
RL Cells 9:0-0(2020).
RN [26]
RP FUNCTION.
RX PubMed=37264229; DOI=10.1038/s41590-023-01523-z;
RA Lin Z., Bashirova A.A., Viard M., Garner L., Quastel M., Beiersdorfer M.,
RA Kasprzak W.K., Akdag M., Yuki Y., Ojeda P., Das S., Andresson T.,
RA Naranbhai V., Horowitz A., McMichael A.J., Hoelzemer A., Gillespie G.M.,
RA Garcia-Beltran W.F., Carrington M.;
RT "HLA class I signal peptide polymorphism determines the level of CD94/NKG2-
RT HLA-E-mediated regulation of effector cell responses.";
RL Nat. Immunol. 24:1087-1097(2023).
RN [27]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 52-179, FUNCTION, AND DISULFIDE
RP BONDS.
RX PubMed=10023772; DOI=10.1016/s1074-7613(00)80008-4;
RA Boyington J.C., Riaz A.N., Patamawenu A., Coligan J.E., Brooks A.G.,
RA Sun P.D.;
RT "Structure of CD94 reveals a novel C-type lectin fold: implications for the
RT NK cell-associated CD94/NKG2 receptors.";
RL Immunity 10:75-82(1999).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 57-179 IN COMPLEX WITH NGK2A,
RP FUNCTION, SUBUNIT, DISULFIDE BONDS, AND MUTAGENESIS OF GLN-79; GLN-112;
RP PHE-114; THR-146; ASN-148; ASN-158; ASN-160; LEU-162; ASP-163; GLU-164 AND
RP ASP-168.
RX PubMed=18083576; DOI=10.1016/j.immuni.2007.10.013;
RA Sullivan L.C., Clements C.S., Beddoe T., Johnson D., Hoare H.L., Lin J.,
RA Huyton T., Hopkins E.J., Reid H.H., Wilce M.C., Kabat J., Borrego F.,
RA Coligan J.E., Rossjohn J., Brooks A.G.;
RT "The heterodimeric assembly of the CD94-NKG2 receptor family and
RT implications for human leukocyte antigen-E recognition.";
RL Immunity 27:900-911(2007).
RN [29]
RP X-RAY CRYSTALLOGRAPHY (4.41 ANGSTROMS) OF 59-179 IN COMPLEX WITH NGK2A,
RP SUBUNIT, AND DISULFIDE BONDS.
RX PubMed=18448674; DOI=10.1073/pnas.0802736105;
RA Kaiser B.K., Pizarro J.C., Kerns J., Strong R.K.;
RT "Structural basis for NKG2A/CD94 recognition of HLA-E.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:6696-6701(2008).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (3.4 ANGSTROMS) OF 57-179 IN COMPLEX WITH NGK2A,
RP SUBUNIT, AND DISULFIDE BONDS.
RX PubMed=18332182; DOI=10.1084/jem.20072525;
RA Petrie E.J., Clements C.S., Lin J., Sullivan L.C., Johnson D., Huyton T.,
RA Heroux A., Hoare H.L., Beddoe T., Reid H.H., Wilce M.C., Brooks A.G.,
RA Rossjohn J.;
RT "CD94-NKG2A recognition of human leukocyte antigen (HLA)-E bound to an HLA
RT class I leader sequence.";
RL J. Exp. Med. 205:725-735(2008).
CC -!- FUNCTION: Immune receptor involved in self-nonself discrimination. In
CC complex with KLRC1 or KLRC2 on cytotoxic and regulatory lymphocyte
CC subsets, recognizes non-classical major histocompatibility (MHC) class
CC Ib molecule HLA-E loaded with self-peptides derived from the signal
CC sequence of classical MHC class Ia and non-classical MHC class Ib
CC molecules (PubMed:9486650, PubMed:10023772, PubMed:18083576,
CC PubMed:18064301, PubMed:9754572, PubMed:37264229). Enables cytotoxic
CC cells to monitor the expression of MHC class I molecules in healthy
CC cells and to tolerate self (PubMed:9430220, PubMed:12387742,
CC PubMed:18064301). Primarily functions as a ligand binding subunit as it
CC lacks the capacity to signal. {ECO:0000269|PubMed:10023772,
CC ECO:0000269|PubMed:12387742, ECO:0000269|PubMed:18064301,
CC ECO:0000269|PubMed:18083576, ECO:0000269|PubMed:37264229,
CC ECO:0000269|PubMed:9430220, ECO:0000269|PubMed:9486650,
CC ECO:0000269|PubMed:9754572}.
CC -!- FUNCTION: KLRD1-KLRC1 acts as an immune inhibitory receptor. Key
CC inhibitory receptor on natural killer (NK) cells that regulates their
CC activation and effector functions (PubMed:9486650, PubMed:9430220,
CC PubMed:9485206, PubMed:30860984). Dominantly counteracts T cell
CC receptor signaling on a subset of memory/effector CD8-positive T cells
CC as part of an antigen-driven response to avoid autoimmunity
CC (PubMed:12387742). On intraepithelial CD8-positive gamma-delta
CC regulatory T cells triggers TGFB1 secretion, which in turn limits the
CC cytotoxic programming of intraepithelial CD8-positive alpha-beta T
CC cells, distinguishing harmless from pathogenic antigens
CC (PubMed:18064301). In HLA-E-rich tumor microenvironment, acts as an
CC immune inhibitory checkpoint and may contribute to progressive loss of
CC effector functions of NK cells and tumor-specific T cells, a state
CC known as cell exhaustion (PubMed:30503213, PubMed:30860984). Upon HLA-
CC E-peptide binding, transmits intracellular signals through KLRC1
CC immunoreceptor tyrosine-based inhibition motifs (ITIMs) by recruiting
CC INPP5D/SHIP-1 and INPPL1/SHIP-2 tyrosine phosphatases to ITIMs, and
CC ultimately opposing signals transmitted by activating receptors through
CC dephosphorylation of proximal signaling molecules (PubMed:9485206,
CC PubMed:12165520). {ECO:0000269|PubMed:12165520,
CC ECO:0000269|PubMed:12387742, ECO:0000269|PubMed:18064301,
CC ECO:0000269|PubMed:30503213, ECO:0000269|PubMed:30860984,
CC ECO:0000269|PubMed:9430220, ECO:0000269|PubMed:9485206,
CC ECO:0000269|PubMed:9486650}.
CC -!- FUNCTION: KLRD1-KLRC2 acts as an immune activating receptor
CC (PubMed:9655483, PubMed:15940674). On cytotoxic lymphocyte subsets
CC recognizes HLA-E loaded with signal sequence-derived peptides from non-
CC classical MHC class Ib HLA-G molecules, likely playing a role in the
CC generation and effector functions of adaptive NK cells and in maternal-
CC fetal tolerance during pregnancy (PubMed:9754572, PubMed:30134159).
CC Regulates the effector functions of terminally differentiated cytotoxic
CC lymphocyte subsets, and in particular may play a role in adaptive NK
CC cell response to viral infection (PubMed:21825173, PubMed:20952657).
CC Upon HLA-E-peptide binding, transmits intracellular signals via the
CC adapter protein TYROBP/DAP12, triggering the phosphorylation of
CC proximal signaling molecules and cell activation (PubMed:9655483,
CC PubMed:15940674). {ECO:0000269|PubMed:15940674,
CC ECO:0000269|PubMed:20952657, ECO:0000269|PubMed:21825173,
CC ECO:0000269|PubMed:30134159, ECO:0000269|PubMed:9655483,
CC ECO:0000269|PubMed:9754572}.
CC -!- FUNCTION: (Microbial infection) Viruses like human cytomegalovirus have
CC evolved an escape mechanism whereby virus-induced down-regulation of
CC host MHC class I molecules is coupled to the binding of viral peptides
CC to HLA-E, restoring HLA-E expression and inducing HLA-E-dependent NK
CC cell immune tolerance to infected cells. Recognizes HLA-E in complex
CC with human cytomegalovirus UL40-derived peptide (VMAPRTLIL) and
CC inhibits NK cell cytotoxicity. {ECO:0000269|PubMed:10669413,
CC ECO:0000269|PubMed:23335510}.
CC -!- FUNCTION: (Microbial infection) May recognize HLA-E in complex with
CC HIV-1 gag/Capsid protein p24-derived peptide (AISPRTLNA) on infected
CC cells and may inhibit NK cell cytotoxicity, a mechanism that allows
CC HIV-1 to escape immune recognition. {ECO:0000269|PubMed:15751767}.
CC -!- FUNCTION: (Microbial infection) Upon SARS-CoV-2 infection, may
CC contribute to functional exhaustion of cytotoxic NK cells and CD8-
CC positive T cells (PubMed:32859121). On NK cells, may recognize HLA-E in
CC complex with SARS-CoV-2 S/Spike protein S1-derived peptide (LQPRTFLL)
CC expressed on the surface of lung epithelial cells, inducing NK cell
CC exhaustion and dampening antiviral immune surveillance
CC (PubMed:32859121). {ECO:0000269|PubMed:32859121}.
CC -!- SUBUNIT: Can form disulfide-bonded heterodimer with NKG2 family members
CC KLRC1 and KLRC2 (PubMed:18083576, PubMed:18332182, PubMed:18448674,
CC PubMed:9655483). KLRD1-KLRC1 heterodimer interacts with peptide-bound
CC HLA-E-B2M heterotrimeric complex. KLRD1 plays a prominent role in
CC directly interacting with HLA-E (PubMed:18083576). KLRD1-KLRC1
CC interacts with much higher affinity with peptide-bound HLA-E-B2M than
CC KLRD1-KLRC2 (PubMed:9486650, PubMed:10428963). Interacts with the
CC adapter protein TYROBP/DAP12; this interaction is required for cell
CC surface expression and cell activation (PubMed:9655483,
CC PubMed:15940674). {ECO:0000269|PubMed:10428963,
CC ECO:0000269|PubMed:18083576, ECO:0000269|PubMed:18332182,
CC ECO:0000269|PubMed:18448674, ECO:0000269|PubMed:9486650,
CC ECO:0000269|PubMed:9655483}.
CC -!- INTERACTION:
CC Q13241; P26715: KLRC1; NbExp=6; IntAct=EBI-9018174, EBI-9018187;
CC Q13241; P26717: KLRC2; NbExp=2; IntAct=EBI-9018174, EBI-3862171;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:20952657,
CC ECO:0000269|PubMed:9485206}; Single-pass type II membrane protein
CC {ECO:0000255}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=CD94-A;
CC IsoId=Q13241-1; Sequence=Displayed;
CC Name=2; Synonyms=CD94-B;
CC IsoId=Q13241-2; Sequence=VSP_003053;
CC Name=3; Synonyms=CD94 alt;
CC IsoId=Q13241-3; Sequence=VSP_003052;
CC -!- TISSUE SPECIFICITY: Expressed in NK cell subsets (at protein level)
CC (PubMed:21825173, PubMed:9430220, PubMed:9485206). Expressed in
CC memory/effector CD8-positive alpha-beta T cell subsets (at protein
CC level) (PubMed:12387742, PubMed:20952657). Expressed in melanoma-
CC specific cytotoxic T cell clones (at protein level) (PubMed:9485206).
CC Expressed in terminally differentiated cytotoxic gamma-delta T cells
CC (at protein level) (PubMed:20952657). KLRD1-KLRC1 and KLRD1-KLRC2 are
CC differentially expressed in NK and T cell populations, with only minor
CC subsets expressing both receptor complexes (at protein level)
CC (PubMed:20952657). {ECO:0000269|PubMed:12387742,
CC ECO:0000269|PubMed:20952657, ECO:0000269|PubMed:21825173,
CC ECO:0000269|PubMed:9430220, ECO:0000269|PubMed:9485206}.
CC -!- WEB RESOURCE: Name=Functional Glycomics Gateway - Glycan Binding;
CC Note=CD94;
CC URL="http://www.functionalglycomics.org/glycomics/GBPServlet?&operationType=view&cbpId=cbp_hum_Ctlect_238";
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DR EMBL; U30610; AAC50291.1; -; mRNA.
DR EMBL; Y14287; CAA74663.1; -; Genomic_DNA.
DR EMBL; Y14288; CAA74663.1; JOINED; Genomic_DNA.
DR EMBL; AJ000673; CAA04230.1; -; Genomic_DNA.
DR EMBL; AJ000001; CAA03845.1; -; mRNA.
DR EMBL; AB009597; BAA24450.1; -; mRNA.
DR EMBL; AB010084; BAA24451.1; -; Genomic_DNA.
DR EMBL; AC022075; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC028009; AAH28009.1; -; mRNA.
DR CCDS; CCDS8621.1; -. [Q13241-1]
DR CCDS; CCDS8622.1; -. [Q13241-3]
DR RefSeq; NP_001107868.1; NM_001114396.1. [Q13241-1]
DR RefSeq; NP_002253.1; NM_002262.3. [Q13241-1]
DR RefSeq; NP_031360.1; NM_007334.2. [Q13241-3]
DR RefSeq; XP_016874780.1; XM_017019291.1.
DR PDB; 1B6E; X-ray; 2.60 A; A=52-179.
DR PDB; 3BDW; X-ray; 2.50 A; A/C=57-179.
DR PDB; 3CDG; X-ray; 3.40 A; E/J=57-179.
DR PDB; 3CII; X-ray; 4.41 A; G/I=59-179.
DR PDBsum; 1B6E; -.
DR PDBsum; 3BDW; -.
DR PDBsum; 3CDG; -.
DR PDBsum; 3CII; -.
DR AlphaFoldDB; Q13241; -.
DR SMR; Q13241; -.
DR BioGRID; 110023; 132.
DR ComplexPortal; CPX-2502; CD94-NKG2A natural killer receptor complex.
DR ComplexPortal; CPX-5901; CD94-NKG2C natural killer receptor complex.
DR ComplexPortal; CPX-5903; CD94-NKG2E natural killer receptor complex.
DR IntAct; Q13241; 5.
DR STRING; 9606.ENSP00000338130; -.
DR UniLectin; Q13241; -.
DR GlyCosmos; Q13241; 2 sites, No reported glycans.
DR GlyGen; Q13241; 2 sites.
DR iPTMnet; Q13241; -.
DR PhosphoSitePlus; Q13241; -.
DR BioMuta; KLRD1; -.
DR DMDM; 334302835; -.
DR jPOST; Q13241; -.
DR MassIVE; Q13241; -.
DR PaxDb; 9606-ENSP00000371333; -.
DR PeptideAtlas; Q13241; -.
DR ProteomicsDB; 59243; -. [Q13241-1]
DR ProteomicsDB; 59244; -. [Q13241-2]
DR ProteomicsDB; 59245; -. [Q13241-3]
DR Antibodypedia; 11712; 927 antibodies from 37 providers.
DR DNASU; 3824; -.
DR Ensembl; ENST00000336164.9; ENSP00000338130.4; ENSG00000134539.17. [Q13241-1]
DR Ensembl; ENST00000350274.9; ENSP00000310929.7; ENSG00000134539.17. [Q13241-3]
DR Ensembl; ENST00000381908.7; ENSP00000371333.4; ENSG00000134539.17. [Q13241-1]
DR GeneID; 3824; -.
DR KEGG; hsa:3824; -.
DR MANE-Select; ENST00000336164.9; ENSP00000338130.4; NM_002262.5; NP_002253.2.
DR UCSC; uc001qxw.5; human. [Q13241-1]
DR AGR; HGNC:6378; -.
DR CTD; 3824; -.
DR DisGeNET; 3824; -.
DR GeneCards; KLRD1; -.
DR HGNC; HGNC:6378; KLRD1.
DR HPA; ENSG00000134539; Tissue enhanced (lymphoid).
DR MIM; 602894; gene.
DR neXtProt; NX_Q13241; -.
DR OpenTargets; ENSG00000134539; -.
DR PharmGKB; PA30167; -.
DR VEuPathDB; HostDB:ENSG00000134539; -.
DR eggNOG; KOG4297; Eukaryota.
DR GeneTree; ENSGT00940000160107; -.
DR InParanoid; Q13241; -.
DR OMA; RFICERK; -.
DR TreeFam; TF336674; -.
DR PathwayCommons; Q13241; -.
DR Reactome; R-HSA-198933; Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell.
DR Reactome; R-HSA-2172127; DAP12 interactions.
DR Reactome; R-HSA-2424491; DAP12 signaling.
DR SignaLink; Q13241; -.
DR BioGRID-ORCS; 3824; 8 hits in 1139 CRISPR screens.
DR ChiTaRS; KLRD1; human.
DR EvolutionaryTrace; Q13241; -.
DR GeneWiki; KLRD1; -.
DR GenomeRNAi; 3824; -.
DR Pharos; Q13241; Tbio.
DR PRO; PR:Q13241; -.
DR Proteomes; UP000005640; Chromosome 12.
DR RNAct; Q13241; Protein.
DR Bgee; ENSG00000134539; Expressed in granulocyte and 106 other cell types or tissues.
DR ExpressionAtlas; Q13241; baseline and differential.
DR Genevisible; Q13241; HS.
DR GO; GO:0009897; C:external side of plasma membrane; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0043235; C:receptor complex; IDA:UniProtKB.
DR GO; GO:0030246; F:carbohydrate binding; IEA:UniProtKB-KW.
DR GO; GO:0062082; F:HLA-E specific inhibitory MHC class Ib receptor activity; IDA:UniProtKB.
DR GO; GO:0023024; F:MHC class I protein complex binding; IPI:UniProtKB.
DR GO; GO:0023030; F:MHC class Ib protein binding, via antigen binding groove; IPI:UniProtKB.
DR GO; GO:1990405; F:protein antigen binding; IDA:UniProtKB.
DR GO; GO:0004888; F:transmembrane signaling receptor activity; IBA:GO_Central.
DR GO; GO:0002250; P:adaptive immune response; IEA:UniProtKB-KW.
DR GO; GO:0007166; P:cell surface receptor signaling pathway; TAS:ProtInc.
DR GO; GO:0002228; P:natural killer cell mediated immunity; IDA:UniProtKB.
DR GO; GO:0045953; P:negative regulation of natural killer cell mediated cytotoxicity; IDA:UniProtKB.
DR GO; GO:0001915; P:negative regulation of T cell mediated cytotoxicity; IDA:UniProtKB.
DR GO; GO:0045954; P:positive regulation of natural killer cell mediated cytotoxicity; IDA:UniProtKB.
DR GO; GO:0032814; P:regulation of natural killer cell activation; NAS:ComplexPortal.
DR GO; GO:0002223; P:stimulatory C-type lectin receptor signaling pathway; IDA:UniProtKB.
DR CDD; cd03593; CLECT_NK_receptors_like; 1.
DR Gene3D; 3.10.100.10; Mannose-Binding Protein A, subunit A; 1.
DR InterPro; IPR001304; C-type_lectin-like.
DR InterPro; IPR016186; C-type_lectin-like/link_sf.
DR InterPro; IPR016187; CTDL_fold.
DR InterPro; IPR033992; NKR-like_CTLD.
DR PANTHER; PTHR22800; C-TYPE LECTIN PROTEINS; 1.
DR PANTHER; PTHR22800:SF246; NATURAL KILLER CELLS ANTIGEN CD94; 1.
DR Pfam; PF00059; Lectin_C; 1.
DR SMART; SM00034; CLECT; 1.
DR SUPFAM; SSF56436; C-type lectin-like; 1.
DR PROSITE; PS50041; C_TYPE_LECTIN_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Adaptive immunity; Alternative splicing; Cell membrane;
KW Disulfide bond; Glycoprotein; Host-virus interaction; Immunity;
KW Innate immunity; Lectin; Membrane; Receptor; Reference proteome;
KW Signal-anchor; Transmembrane; Transmembrane helix.
FT CHAIN 1..179
FT /note="Natural killer cells antigen CD94"
FT /id="PRO_0000046587"
FT TOPO_DOM 1..10
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 11..31
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 32..179
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT DOMAIN 68..175
FT /note="C-type lectin"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00040"
FT CARBOHYD 83
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 132
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 58..70
FT /evidence="ECO:0000269|PubMed:18083576,
FT ECO:0000269|PubMed:18332182"
FT DISULFID 59
FT /note="Interchain (with C-116 in KLRC1/NGK2A)"
FT /evidence="ECO:0000269|PubMed:18083576,
FT ECO:0000269|PubMed:18332182"
FT DISULFID 61..72
FT /evidence="ECO:0000269|PubMed:10023772,
FT ECO:0000269|PubMed:18083576, ECO:0000269|PubMed:18332182,
FT ECO:0000269|PubMed:18448674"
FT DISULFID 89..174
FT /evidence="ECO:0000269|PubMed:10023772,
FT ECO:0000269|PubMed:18083576, ECO:0000269|PubMed:18332182,
FT ECO:0000269|PubMed:18448674"
FT DISULFID 152..166
FT /evidence="ECO:0000269|PubMed:10023772,
FT ECO:0000269|PubMed:18083576, ECO:0000269|PubMed:18332182,
FT ECO:0000269|PubMed:18448674"
FT VAR_SEQ 1..34
FT /note="MAVFKTTLWRLISGTLGIICLSLMSTLGILLKNS -> MAA (in
FT isoform 3)"
FT /evidence="ECO:0000303|PubMed:9601951"
FT /id="VSP_003052"
FT VAR_SEQ 105
FT /note="L -> LQ (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_003053"
FT VARIANT 25
FT /note="S -> A (in dbSNP:rs10772256)"
FT /evidence="ECO:0000269|PubMed:15489334,
FT ECO:0000269|PubMed:7589107, ECO:0000269|PubMed:9472066"
FT /id="VAR_050103"
FT MUTAGEN 79
FT /note="Q->A: Has no impact on the affinity for HLA-E."
FT /evidence="ECO:0000269|PubMed:18083576"
FT MUTAGEN 112
FT /note="Q->A: Abolishes binding to HLA-E."
FT /evidence="ECO:0000269|PubMed:18083576"
FT MUTAGEN 114
FT /note="F->A: Abolishes binding to HLA-E."
FT /evidence="ECO:0000269|PubMed:18083576"
FT MUTAGEN 146
FT /note="T->A: Has no impact on the affinity for HLA-E."
FT /evidence="ECO:0000269|PubMed:18083576"
FT MUTAGEN 148
FT /note="N->A: Has no impact on the affinity for HLA-E."
FT /evidence="ECO:0000269|PubMed:18083576"
FT MUTAGEN 158
FT /note="N->A: Has no impact on the affinity for HLA-E."
FT /evidence="ECO:0000269|PubMed:18083576"
FT MUTAGEN 160
FT /note="N->A: Abolishes binding to HLA-E."
FT /evidence="ECO:0000269|PubMed:18083576"
FT MUTAGEN 162
FT /note="L->A: Abolishes binding to HLA-E."
FT /evidence="ECO:0000269|PubMed:18083576"
FT MUTAGEN 163
FT /note="D->A: Impairs binding to HLA-E."
FT /evidence="ECO:0000269|PubMed:18083576"
FT MUTAGEN 164
FT /note="E->A: Impairs binding to HLA-E."
FT /evidence="ECO:0000269|PubMed:18083576"
FT MUTAGEN 168
FT /note="D->A: Reduces binding to HLA-E."
FT /evidence="ECO:0000269|PubMed:18083576"
FT TURN 62..64
FT /evidence="ECO:0007829|PDB:3BDW"
FT STRAND 66..68
FT /evidence="ECO:0007829|PDB:3BDW"
FT STRAND 71..75
FT /evidence="ECO:0007829|PDB:3BDW"
FT HELIX 82..91
FT /evidence="ECO:0007829|PDB:3BDW"
FT HELIX 102..108
FT /evidence="ECO:0007829|PDB:3BDW"
FT STRAND 118..122
FT /evidence="ECO:0007829|PDB:3BDW"
FT TURN 123..126
FT /evidence="ECO:0007829|PDB:3BDW"
FT STRAND 127..130
FT /evidence="ECO:0007829|PDB:3BDW"
FT TURN 138..140
FT /evidence="ECO:0007829|PDB:3BDW"
FT HELIX 142..146
FT /evidence="ECO:0007829|PDB:3BDW"
FT STRAND 151..156
FT /evidence="ECO:0007829|PDB:3BDW"
FT TURN 157..159
FT /evidence="ECO:0007829|PDB:3BDW"
FT STRAND 160..164
FT /evidence="ECO:0007829|PDB:3BDW"
FT STRAND 170..176
FT /evidence="ECO:0007829|PDB:3BDW"
SQ SEQUENCE 179 AA; 20513 MW; 01634D3832D4B1A7 CRC64;
MAVFKTTLWR LISGTLGIIC LSLMSTLGIL LKNSFTKLSI EPAFTPGPNI ELQKDSDCCS
CQEKWVGYRC NCYFISSEQK TWNESRHLCA SQKSSLLQLQ NTDELDFMSS SQQFYWIGLS
YSEEHTAWLW ENGSALSQYL FPSFETFNTK NCIAYNPNGN ALDESCEDKN RYICKQQLI
//