ID   NKG2A_HUMAN             Reviewed;         233 AA.
AC   P26715;
DT   01-AUG-1992, integrated into UniProtKB/Swiss-Prot.
DT   11-JAN-2011, sequence version 2.
DT   24-JAN-2024, entry version 200.
DE   RecName: Full=NKG2-A/NKG2-B type II integral membrane protein;
DE   AltName: Full=CD159 antigen-like family member A;
DE   AltName: Full=NK cell receptor A;
DE   AltName: Full=NKG2-A/B-activating NK receptor;
DE   AltName: CD_antigen=CD159a;
GN   Name=KLRC1; Synonyms=NKG2A {ECO:0000303|PubMed:18083576};
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] (ISOFORMS NKG2-A AND NKG2-B), AND VARIANT
RP   SER-29.
RX   PubMed=2007850; DOI=10.1084/jem.173.4.1017;
RA   Houchins J.P., Yabe T., McSherry C., Bach F.H.;
RT   "DNA sequence analysis of NKG2, a family of related cDNA clones encoding
RT   type II integral membrane proteins on human natural killer cells.";
RL   J. Exp. Med. 173:1017-1020(1991).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS NKG2-A AND NKG2-B), AND VARIANT
RP   SER-29.
RX   PubMed=8753859; DOI=10.1007/bf02602558;
RA   Plougastel B., Jones T., Trowsdale J.;
RT   "Genomic structure, chromosome location, and alternative splicing of the
RT   human NKG2A gene.";
RL   Immunogenetics 44:286-291(1996).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS NKG2-A AND NKG2-B), AND VARIANT
RP   SER-29.
RX   PubMed=9598306; DOI=10.1006/geno.1997.5197;
RA   Plougastel B., Trowsdale J.;
RT   "Sequence analysis of a 62-kb region overlapping the human KLRC cluster of
RT   genes.";
RL   Genomics 49:193-199(1998).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT SER-29.
RA   Kothapalli R., Kusmartseva I., Loughran T.P. Jr.;
RT   "Identification and characterization of the NKG2A gene from large granular
RT   lymphocytic leukemia (LGL) cells.";
RL   Submitted (DEC-2001) to the EMBL/GenBank/DDBJ databases.
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] (ISOFORMS NKG2-A AND NKG2-B), AND
RP   VARIANT SER-29.
RC   TISSUE=Blood, and Kidney;
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, INTERACTION WITH INPP5D AND INPPL1, 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=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   [10]
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   [11]
RP   FUNCTION, TISSUE SPECIFICITY, AND INDUCTION.
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   [12]
RP   FUNCTION, INTERACTION WITH INPP5D, SUBCELLULAR LOCATION, DOMAIN,
RP   PHOSPHORYLATION AT TYR-8 AND TYR-40, AND MUTAGENESIS OF VAL-6; TYR-8;
RP   ILE-38 AND TYR-40.
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   [13]
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   [14]
RP   FUNCTION, AND TISSUE SPECIFICITY.
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   [15]
RP   TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
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   [16]
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   [17]
RP   FUNCTION, AND TISSUE SPECIFICITY.
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   [18]
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   [19]
RP   FUNCTION (MICROBIAL INFECTION).
RX   PubMed=32203188; DOI=10.1038/s41423-020-0402-2;
RA   Zheng M., Gao Y., Wang G., Song G., Liu S., Sun D., Xu Y., Tian Z.;
RT   "Functional exhaustion of antiviral lymphocytes in COVID-19 patients.";
RL   Cell. Mol. Immunol. 17:533-535(2020).
RN   [20]
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   [21]
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   [22]
RP   X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 113-232 IN COMPLEX WITH KLRD1,
RP   SUBUNIT, DISULFIDE BONDS, MUTAGENESIS OF ARG-137; MET-163;
RP   167-SER--SER-170; SER-172; ASP-200; ASP-202; GLN-212; VAL-213; ARG-215;
RP   LYS-217; GLN-220 AND SER-223, AND FUNCTION.
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   [23]
RP   X-RAY CRYSTALLOGRAPHY (3.4 ANGSTROMS) OF 113-232 IN COMPLEX WITH KLRD1,
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).
RN   [24]
RP   X-RAY CRYSTALLOGRAPHY (4.41 ANGSTROMS) OF 113-232 IN COMPLEX WITH KLRD1,
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).
CC   -!- FUNCTION: Immune inhibitory receptor involved in self-nonself
CC       discrimination. In complex with KLRD1 on cytotoxic and regulatory
CC       lymphocyte subsets, recognizes non-classical major histocompatibility
CC       (MHC) class Ib molecule HLA-E loaded with self-peptides derived from
CC       the signal sequence of classical MHC class Ia molecules. Enables
CC       cytotoxic cells to monitor the expression of MHC class I molecules in
CC       healthy cells and to tolerate self (PubMed:9486650, PubMed:18083576,
CC       PubMed:9430220, PubMed:37264229). Upon HLA-E-peptide binding, transmits
CC       intracellular signals through two immunoreceptor tyrosine-based
CC       inhibition motifs (ITIMs) by recruiting INPP5D/SHP-1 and INPPL1/SHP-2
CC       tyrosine phosphatases to ITIMs, and ultimately opposing signals
CC       transmitted by activating receptors through dephosphorylation of
CC       proximal signaling molecules (PubMed:9485206, PubMed:12165520). 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).
CC       {ECO:0000269|PubMed:12165520, ECO:0000269|PubMed:12387742,
CC       ECO:0000269|PubMed:18064301, ECO:0000269|PubMed:18083576,
CC       ECO:0000269|PubMed:30503213, ECO:0000269|PubMed:30860984,
CC       ECO:0000269|PubMed:37264229, ECO:0000269|PubMed:9430220,
CC       ECO:0000269|PubMed:9485206, ECO:0000269|PubMed:9486650}.
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:32203188, PubMed:32859121). On NK cells, may
CC       recognize HLA-E in complex with SARS-CoV-2 S/Spike protein S1-derived
CC       peptide (LQPRTFLL) expressed on the surface of lung epithelial cells,
CC       inducing NK cell exhaustion and dampening antiviral immune surveillance
CC       (PubMed:32859121). {ECO:0000269|PubMed:32203188,
CC       ECO:0000269|PubMed:32859121}.
CC   -!- SUBUNIT: Heterodimer with KLRD1; disulfide-linked (PubMed:18083576,
CC       PubMed:18332182, PubMed:18448674). KLRD1-KLRC1 heterodimer interacts
CC       with peptide-bound HLA-E-B2M heterotrimeric complex (PubMed:18083576).
CC       Competes with KLRC2 for its interaction with HLA-E (PubMed:18083576).
CC       Interacts (via ITIM) with INPP5D/SHIP-1 and INPPL1/SHIP-2 (via SH2
CC       domain). {ECO:0000269|PubMed:12165520, ECO:0000269|PubMed:18083576,
CC       ECO:0000269|PubMed:18332182, ECO:0000269|PubMed:18448674,
CC       ECO:0000269|PubMed:9485206}.
CC   -!- INTERACTION:
CC       P26715; Q99437: ATP6V0B; NbExp=3; IntAct=EBI-9018187, EBI-3904417;
CC       P26715; P27449: ATP6V0C; NbExp=3; IntAct=EBI-9018187, EBI-721179;
CC       P26715; O95393: BMP10; NbExp=3; IntAct=EBI-9018187, EBI-3922513;
CC       P26715; Q6PL45-2: BRICD5; NbExp=3; IntAct=EBI-9018187, EBI-12244618;
CC       P26715; P27797: CALR; NbExp=3; IntAct=EBI-9018187, EBI-1049597;
CC       P26715; P48509: CD151; NbExp=3; IntAct=EBI-9018187, EBI-10210332;
CC       P26715; P27701: CD82; NbExp=3; IntAct=EBI-9018187, EBI-682379;
CC       P26715; Q15078: CDK5R1; NbExp=3; IntAct=EBI-9018187, EBI-746189;
CC       P26715; Q99675: CGRRF1; NbExp=3; IntAct=EBI-9018187, EBI-2130213;
CC       P26715; O75508: CLDN11; NbExp=3; IntAct=EBI-9018187, EBI-12820543;
CC       P26715; Q9UHP7-3: CLEC2D; NbExp=4; IntAct=EBI-9018187, EBI-11749983;
CC       P26715; Q9BXN2-6: CLEC7A; NbExp=3; IntAct=EBI-9018187, EBI-11989440;
CC       P26715; A0PK11: CLRN2; NbExp=3; IntAct=EBI-9018187, EBI-12813623;
CC       P26715; Q4LDR2: CTXN3; NbExp=3; IntAct=EBI-9018187, EBI-12019274;
CC       P26715; Q8NBI2: CYB561A3; NbExp=3; IntAct=EBI-9018187, EBI-10269179;
CC       P26715; P36957: DLST; NbExp=3; IntAct=EBI-9018187, EBI-351007;
CC       P26715; P54849: EMP1; NbExp=3; IntAct=EBI-9018187, EBI-4319440;
CC       P26715; P54852: EMP3; NbExp=4; IntAct=EBI-9018187, EBI-3907816;
CC       P26715; Q7Z2K6: ERMP1; NbExp=3; IntAct=EBI-9018187, EBI-10976398;
CC       P26715; P29033: GJB2; NbExp=3; IntAct=EBI-9018187, EBI-3905204;
CC       P26715; Q9NTQ9: GJB4; NbExp=3; IntAct=EBI-9018187, EBI-12831526;
CC       P26715; O95452: GJB6; NbExp=3; IntAct=EBI-9018187, EBI-13345609;
CC       P26715; Q9BZJ8: GPR61; NbExp=3; IntAct=EBI-9018187, EBI-12808020;
CC       P26715; Q9Y287: ITM2B; NbExp=3; IntAct=EBI-9018187, EBI-2866431;
CC       P26715; Q13241: KLRD1; NbExp=6; IntAct=EBI-9018187, EBI-9018174;
CC       P26715; Q96E93: KLRG1; NbExp=3; IntAct=EBI-9018187, EBI-750770;
CC       P26715; Q8N112: LSMEM2; NbExp=3; IntAct=EBI-9018187, EBI-10264855;
CC       P26715; P21145: MAL; NbExp=6; IntAct=EBI-9018187, EBI-3932027;
CC       P26715; Q13021: MALL; NbExp=3; IntAct=EBI-9018187, EBI-750078;
CC       P26715; Q5J8X5: MS4A13; NbExp=3; IntAct=EBI-9018187, EBI-12070086;
CC       P26715; Q8TDX7: NEK7; NbExp=3; IntAct=EBI-9018187, EBI-1055945;
CC       P26715; Q16617: NKG7; NbExp=3; IntAct=EBI-9018187, EBI-3919611;
CC       P26715; P60201-2: PLP1; NbExp=3; IntAct=EBI-9018187, EBI-12188331;
CC       P26715; Q01453: PMP22; NbExp=6; IntAct=EBI-9018187, EBI-2845982;
CC       P26715; P11686: SFTPC; NbExp=3; IntAct=EBI-9018187, EBI-10197617;
CC       P26715; Q6ZP80: TMEM182; NbExp=3; IntAct=EBI-9018187, EBI-10255122;
CC       P26715; E9PQX1: TMEM262; NbExp=3; IntAct=EBI-9018187, EBI-17180389;
CC       P26715; Q969K7: TMEM54; NbExp=3; IntAct=EBI-9018187, EBI-3922833;
CC       P26715; Q6ZT21: TMPPE; NbExp=3; IntAct=EBI-9018187, EBI-11724433;
CC       P26715; Q5TGU0: TSPO2; NbExp=3; IntAct=EBI-9018187, EBI-12195249;
CC       P26715; Q5BVD1: TTMP; NbExp=3; IntAct=EBI-9018187, EBI-10243654;
CC       P26715; Q9H1C4: UNC93B1; NbExp=3; IntAct=EBI-9018187, EBI-4401271;
CC       P26715; O75841: UPK1B; NbExp=3; IntAct=EBI-9018187, EBI-12237619;
CC       P26715; O95183: VAMP5; NbExp=3; IntAct=EBI-9018187, EBI-10191195;
CC       P26715; Q9UEU0: VTI1B; NbExp=3; IntAct=EBI-9018187, EBI-723716;
CC       P26715; O95159: ZFPL1; NbExp=3; IntAct=EBI-9018187, EBI-718439;
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:12165520,
CC       ECO:0000269|PubMed:20952657}; Single-pass type II membrane protein
CC       {ECO:0000255}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=NKG2-A;
CC         IsoId=P26715-1; Sequence=Displayed;
CC       Name=NKG2-B;
CC         IsoId=P26715-2; Sequence=VSP_003062;
CC   -!- TISSUE SPECIFICITY: Predominantly expressed in NK cells (at protein
CC       level) (PubMed:9430220, PubMed:9485206, PubMed:20952657). Expressed in
CC       intraepithelial CD8-positive T cell subsets with higher frequency in
CC       gamma-delta T cells than alpha-beta T cells (at protein level)
CC       (PubMed:18064301). Expressed in memory gamma-delta T cells (at protein
CC       level) (PubMed:20952657). Restricted to a subset of memory/effector
CC       CD8-positive alpha-beta T cells (at protein level) (PubMed:12387742).
CC       Expressed in intratumoral NK and CD8-positive T cells
CC       (PubMed:30503213). Expressed in melanoma-specific cytotoxic T cell
CC       clones (at protein level) (PubMed:9485206). KLRD1-KLRC1 and KLRD1-KLRC2
CC       are differentially expressed in NK and T cell populations, with only
CC       minor subsets expressing both receptor complexes (at protein level)
CC       (PubMed:20952657). {ECO:0000269|PubMed:12387742,
CC       ECO:0000269|PubMed:18064301, ECO:0000269|PubMed:20952657,
CC       ECO:0000269|PubMed:30503213, ECO:0000269|PubMed:9430220,
CC       ECO:0000269|PubMed:9485206}.
CC   -!- INDUCTION: Up-regulated in memory CD8-positive alpha-beta T cell clones
CC       upon antigen-specific stimulation. {ECO:0000269|PubMed:12387742}.
CC   -!- DOMAIN: The cytosolic N-terminus contains two immunoreceptor tyrosine-
CC       based inhibitory motifs (ITIMs), which are essential for the
CC       association with INPP5D/SHIP-1 and INPPL1/SHIP-2 phosphatases and
CC       functional inhibition. {ECO:0000269|PubMed:12165520}.
CC   -!- PTM: Phosphorylated. {ECO:0000269|PubMed:12165520}.
CC   -!- WEB RESOURCE: Name=Functional Glycomics Gateway - Glycan Binding;
CC       Note=NKG-2A;
CC       URL="http://www.functionalglycomics.org/glycomics/GBPServlet?&operationType=view&cbpId=cbp_hum_Ctlect_245";
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DR   EMBL; X54867; CAA38649.1; -; mRNA.
DR   EMBL; X54868; CAA38650.1; -; mRNA.
DR   EMBL; U54786; AAB17133.1; -; Genomic_DNA.
DR   EMBL; U54783; AAB17133.1; JOINED; Genomic_DNA.
DR   EMBL; U54784; AAB17133.1; JOINED; Genomic_DNA.
DR   EMBL; U54785; AAB17133.1; JOINED; Genomic_DNA.
DR   EMBL; AF023840; AAC17488.1; -; Genomic_DNA.
DR   EMBL; AF461812; AAL65234.1; -; mRNA.
DR   EMBL; AC068775; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC012550; AAH12550.1; -; mRNA.
DR   EMBL; BC053840; AAH53840.1; -; mRNA.
DR   CCDS; CCDS8625.1; -. [P26715-1]
DR   CCDS; CCDS8626.1; -. [P26715-2]
DR   PIR; PT0372; PT0372.
DR   RefSeq; NP_002250.1; NM_002259.4. [P26715-1]
DR   RefSeq; NP_015567.1; NM_007328.3. [P26715-2]
DR   RefSeq; NP_998822.1; NM_213657.2. [P26715-2]
DR   RefSeq; NP_998823.1; NM_213658.2. [P26715-1]
DR   PDB; 2RMX; NMR; -; B=1-15.
DR   PDB; 2YU7; NMR; -; B=33-47.
DR   PDB; 3BDW; X-ray; 2.50 A; B/D=113-232.
DR   PDB; 3CDG; X-ray; 3.40 A; F/K=113-232.
DR   PDB; 3CII; X-ray; 4.41 A; H/J=113-232.
DR   PDBsum; 2RMX; -.
DR   PDBsum; 2YU7; -.
DR   PDBsum; 3BDW; -.
DR   PDBsum; 3CDG; -.
DR   PDBsum; 3CII; -.
DR   AlphaFoldDB; P26715; -.
DR   SMR; P26715; -.
DR   BioGRID; 110020; 163.
DR   ComplexPortal; CPX-2502; CD94-NKG2A natural killer receptor complex.
DR   ELM; P26715; -.
DR   IntAct; P26715; 48.
DR   STRING; 9606.ENSP00000438038; -.
DR   ChEMBL; CHEMBL4630892; -.
DR   GuidetoPHARMACOLOGY; 2849; -.
DR   UniLectin; P26715; -.
DR   GlyCosmos; P26715; 4 sites, No reported glycans.
DR   GlyGen; P26715; 5 sites, 1 O-linked glycan (1 site).
DR   iPTMnet; P26715; -.
DR   PhosphoSitePlus; P26715; -.
DR   BioMuta; KLRC1; -.
DR   DMDM; 317373399; -.
DR   jPOST; P26715; -.
DR   MassIVE; P26715; -.
DR   MaxQB; P26715; -.
DR   PaxDb; 9606-ENSP00000438038; -.
DR   PeptideAtlas; P26715; -.
DR   ProteomicsDB; 54362; -. [P26715-1]
DR   ProteomicsDB; 54363; -. [P26715-2]
DR   ABCD; P26715; 1 sequenced antibody.
DR   Antibodypedia; 23336; 665 antibodies from 36 providers.
DR   DNASU; 3821; -.
DR   Ensembl; ENST00000347831.9; ENSP00000256965.7; ENSG00000134545.14. [P26715-2]
DR   Ensembl; ENST00000359151.8; ENSP00000352064.3; ENSG00000134545.14. [P26715-1]
DR   Ensembl; ENST00000408006.7; ENSP00000385304.3; ENSG00000134545.14. [P26715-2]
DR   Ensembl; ENST00000544822.2; ENSP00000438038.1; ENSG00000134545.14. [P26715-1]
DR   GeneID; 3821; -.
DR   KEGG; hsa:3821; -.
DR   MANE-Select; ENST00000359151.8; ENSP00000352064.3; NM_002259.5; NP_002250.2.
DR   UCSC; uc001qyl.5; human. [P26715-1]
DR   AGR; HGNC:6374; -.
DR   CTD; 3821; -.
DR   DisGeNET; 3821; -.
DR   GeneCards; KLRC1; -.
DR   HGNC; HGNC:6374; KLRC1.
DR   HPA; ENSG00000134545; Tissue enhanced (lymphoid).
DR   MIM; 161555; gene.
DR   neXtProt; NX_P26715; -.
DR   OpenTargets; ENSG00000134545; -.
DR   PharmGKB; PA30163; -.
DR   VEuPathDB; HostDB:ENSG00000134545; -.
DR   eggNOG; ENOG502S6IE; Eukaryota.
DR   GeneTree; ENSGT00940000164619; -.
DR   HOGENOM; CLU_049894_9_2_1; -.
DR   InParanoid; P26715; -.
DR   OMA; ICKHQAL; -.
DR   OrthoDB; 3816439at2759; -.
DR   PhylomeDB; P26715; -.
DR   TreeFam; TF336674; -.
DR   PathwayCommons; P26715; -.
DR   Reactome; R-HSA-198933; Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell.
DR   SignaLink; P26715; -.
DR   SIGNOR; P26715; -.
DR   BioGRID-ORCS; 3821; 6 hits in 1117 CRISPR screens.
DR   EvolutionaryTrace; P26715; -.
DR   GenomeRNAi; 3821; -.
DR   Pharos; P26715; Tbio.
DR   PRO; PR:P26715; -.
DR   Proteomes; UP000005640; Chromosome 12.
DR   RNAct; P26715; Protein.
DR   Bgee; ENSG00000134545; Expressed in granulocyte and 93 other cell types or tissues.
DR   ExpressionAtlas; P26715; baseline and differential.
DR   Genevisible; P26715; 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:0062080; F:inhibitory MHC class Ib receptor activity; IDA:UniProtKB.
DR   GO; GO:0023024; F:MHC class I protein complex binding; IPI: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:0002305; P:CD8-positive, gamma-delta intraepithelial T cell differentiation; IDA:UniProtKB.
DR   GO; GO:0007166; P:cell surface receptor signaling pathway; TAS:ProtInc.
DR   GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR   GO; GO:0002769; P:natural killer cell inhibitory signaling pathway; 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; IBA:GO_Central.
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; IBA:GO_Central.
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:SF242; NKG2-A/NKG2-B TYPE II INTEGRAL MEMBRANE PROTEIN; 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; Phosphoprotein; Receptor;
KW   Reference proteome; Signal-anchor; Transmembrane; Transmembrane helix.
FT   CHAIN           1..233
FT                   /note="NKG2-A/NKG2-B type II integral membrane protein"
FT                   /id="PRO_0000046659"
FT   TOPO_DOM        1..70
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        71..93
FT                   /note="Helical; Signal-anchor for type II membrane protein"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        94..233
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   DOMAIN          118..231
FT                   /note="C-type lectin"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00040"
FT   REGION          1..29
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           6..11
FT                   /note="Immunoreceptor tyrosine-based inhibition motif
FT                   (ITIM)"
FT                   /evidence="ECO:0000269|PubMed:12165520"
FT   MOTIF           38..43
FT                   /note="Immunoreceptor tyrosine-based inhibition motif
FT                   (ITIM)"
FT                   /evidence="ECO:0000269|PubMed:12165520"
FT   COMPBIAS        1..16
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOD_RES         8
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000269|PubMed:12165520"
FT   MOD_RES         40
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000269|PubMed:12165520"
FT   CARBOHYD        102
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        103
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        151
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        180
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        116
FT                   /note="Interchain (with C-59 in KLRD1)"
FT                   /evidence="ECO:0000269|PubMed:18083576"
FT   DISULFID        119..130
FT                   /evidence="ECO:0000269|PubMed:18083576"
FT   DISULFID        147..229
FT                   /evidence="ECO:0000269|PubMed:18083576"
FT   DISULFID        208..221
FT                   /evidence="ECO:0000269|PubMed:18083576"
FT   VAR_SEQ         96..113
FT                   /note="Missing (in isoform NKG2-B)"
FT                   /evidence="ECO:0000303|PubMed:15489334,
FT                   ECO:0000303|PubMed:2007850"
FT                   /id="VSP_003062"
FT   VARIANT         29
FT                   /note="N -> S (in dbSNP:rs2253849)"
FT                   /evidence="ECO:0000269|PubMed:15489334,
FT                   ECO:0000269|PubMed:2007850, ECO:0000269|PubMed:8753859,
FT                   ECO:0000269|PubMed:9598306, ECO:0000269|Ref.4"
FT                   /id="VAR_050120"
FT   MUTAGEN         6
FT                   /note="V->A: Decreases interaction with INPP5D/SHIP-1; when
FT                   associated A-38."
FT                   /evidence="ECO:0000269|PubMed:12165520"
FT   MUTAGEN         8
FT                   /note="Y->F: Impairs phosphorylation, interaction with
FT                   INPP5D/SHIP-1 and NK cell functional inhibition; when
FT                   associated F-40."
FT                   /evidence="ECO:0000269|PubMed:12165520"
FT   MUTAGEN         38
FT                   /note="I->A: Decreases interaction with INPP5D/SHIP-1; when
FT                   associated A-6."
FT                   /evidence="ECO:0000269|PubMed:12165520"
FT   MUTAGEN         40
FT                   /note="Y->F: Impairs phosphorylation, interaction with
FT                   INPP5D/SHIP-1 and NK cell functional inhibition; when
FT                   associated F-8."
FT                   /evidence="ECO:0000269|PubMed:12165520"
FT   MUTAGEN         137
FT                   /note="R->A: Reduces binding to HLA-E."
FT                   /evidence="ECO:0000269|PubMed:18083576"
FT   MUTAGEN         163
FT                   /note="M->I: Has no impact on the affinity for HLA-E."
FT                   /evidence="ECO:0000269|PubMed:18083576"
FT   MUTAGEN         167..170
FT                   /note="SIIS->ASIL: Impairs binding to HLA-E."
FT                   /evidence="ECO:0000269|PubMed:18083576"
FT   MUTAGEN         172
FT                   /note="S->A: Has no impact on the affinity for HLA-E."
FT                   /evidence="ECO:0000269|PubMed:18083576"
FT   MUTAGEN         200
FT                   /note="D->A: Has no impact on the affinity for HLA-E."
FT                   /evidence="ECO:0000269|PubMed:18083576"
FT   MUTAGEN         202
FT                   /note="D->A: Has no impact on the affinity for HLA-E."
FT                   /evidence="ECO:0000269|PubMed:18083576"
FT   MUTAGEN         212
FT                   /note="Q->A: Reduces binding to HLA-E."
FT                   /evidence="ECO:0000269|PubMed:18083576"
FT   MUTAGEN         213
FT                   /note="V->A: Has no impact on the affinity for HLA-E."
FT                   /evidence="ECO:0000269|PubMed:18083576"
FT   MUTAGEN         215
FT                   /note="R->A: Reduces binding to HLA-E."
FT                   /evidence="ECO:0000269|PubMed:18083576"
FT   MUTAGEN         217
FT                   /note="K->A: Reduces binding to HLA-E."
FT                   /evidence="ECO:0000269|PubMed:18083576"
FT   MUTAGEN         220
FT                   /note="Q->A: Has little impact on affinity for HLA-E."
FT                   /evidence="ECO:0000269|PubMed:18083576"
FT   MUTAGEN         223
FT                   /note="S->A: Has no impact on affinity for HLA-E."
FT                   /evidence="ECO:0000269|PubMed:18083576"
FT   STRAND          117..119
FT                   /evidence="ECO:0007829|PDB:3CDG"
FT   STRAND          124..138
FT                   /evidence="ECO:0007829|PDB:3BDW"
FT   HELIX           140..149
FT                   /evidence="ECO:0007829|PDB:3BDW"
FT   STRAND          152..154
FT                   /evidence="ECO:0007829|PDB:3BDW"
FT   HELIX           160..169
FT                   /evidence="ECO:0007829|PDB:3BDW"
FT   STRAND          171..178
FT                   /evidence="ECO:0007829|PDB:3BDW"
FT   STRAND          191..193
FT                   /evidence="ECO:0007829|PDB:3BDW"
FT   STRAND          208..219
FT                   /evidence="ECO:0007829|PDB:3BDW"
FT   STRAND          225..230
FT                   /evidence="ECO:0007829|PDB:3BDW"
SQ   SEQUENCE   233 AA;  26314 MW;  93879A5C8D110C62 CRC64;
     MDNQGVIYSD LNLPPNPKRQ QRKPKGNKNS ILATEQEITY AELNLQKASQ DFQGNDKTYH
     CKDLPSAPEK LIVGILGIIC LILMASVVTI VVIPSTLIQR HNNSSLNTRT QKARHCGHCP
     EEWITYSNSC YYIGKERRTW EESLLACTSK NSSLLSIDNE EEMKFLSIIS PSSWIGVFRN
     SSHHPWVTMN GLAFKHEIKD SDNAELNCAV LQVNRLKSAQ CGSSIIYHCK HKL
//