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 05-FEB-2025, entry version 206.
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:18083576, PubMed:37264229,
CC PubMed:9430220, PubMed:9486650). 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:12165520, PubMed:9485206). Key
CC inhibitory receptor on natural killer (NK) cells that regulates their
CC activation and effector functions (PubMed:30860984, PubMed:9430220,
CC PubMed:9485206, PubMed:9486650). Dominantly counteracts T cell receptor
CC signaling on a subset of memory/effector CD8-positive T cells as part
CC of an antigen-driven response to avoid autoimmunity (PubMed:12387742).
CC On intraepithelial CD8-positive gamma-delta regulatory T cells triggers
CC TGFB1 secretion, which in turn limits the cytotoxic programming of
CC intraepithelial CD8-positive alpha-beta T cells, distinguishing
CC harmless from pathogenic antigens (PubMed:18064301). In HLA-E-rich
CC tumor microenvironment, acts as an immune inhibitory checkpoint and may
CC contribute to progressive loss of effector functions of NK cells and
CC tumor-specific T cells, a state known as cell exhaustion
CC (PubMed:30503213, PubMed:30860984). {ECO:0000269|PubMed:12165520,
CC ECO:0000269|PubMed:12387742, ECO:0000269|PubMed:18064301,
CC ECO:0000269|PubMed:18083576, ECO:0000269|PubMed:30503213,
CC ECO:0000269|PubMed:30860984, ECO:0000269|PubMed:37264229,
CC ECO:0000269|PubMed:9430220, ECO:0000269|PubMed:9485206,
CC 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:20952657, PubMed:9430220, PubMed:9485206). 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; 164.
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 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; 686 antibodies from 37 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; ITSWIPV; -.
DR OrthoDB; 10059571at2759; -.
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 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 FunFam; 3.10.100.10:FF:000071; NKG2-A/NKG2-B type II integral membrane protein; 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; IPR050919; NKG2/CD94_NK_receptors.
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;
KW Proteomics identification; Receptor; Reference proteome; Signal-anchor;
KW 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 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
//