CD244_HUMAN
ID CD244_HUMAN Reviewed; 370 AA.
AC Q9BZW8; Q5VYI2; Q5VYI6; Q5VYI7; Q96T47; Q9NQD2; Q9NQD3; Q9Y288;
DT 24-MAY-2004, integrated into UniProtKB/Swiss-Prot.
DT 24-MAY-2004, sequence version 2.
DT 03-AUG-2022, entry version 179.
DE RecName: Full=Natural killer cell receptor 2B4;
DE AltName: Full=NK cell activation-inducing ligand;
DE Short=NAIL;
DE AltName: Full=NK cell type I receptor protein 2B4;
DE Short=NKR2B4;
DE Short=h2B4;
DE AltName: Full=SLAM family member 4;
DE Short=SLAMF4;
DE AltName: Full=Signaling lymphocytic activation molecule 4;
DE AltName: CD_antigen=CD244;
DE Flags: Precursor;
GN Name=CD244; Synonyms=2B4;
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 2), FUNCTION, AND INTERACTION WITH
RP CD48.
RX PubMed=10359122;
RX DOI=10.1002/(sici)1521-4141(199905)29:05<1676::aid-immu1676>3.0.co;2-y;
RA Nakajima H., Cella M., Langen H., Friedlein A., Colonna M.;
RT "Activating interactions in human NK cell recognition: the role of 2B4-
RT CD48.";
RL Eur. J. Immunol. 29:1676-1683(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), PROTEIN SEQUENCE OF N-TERMINUS,
RP TISSUE SPECIFICITY, AND INTERACTION WITH CD48.
RX PubMed=10556801;
RX DOI=10.1002/(sici)1521-4141(199911)29:11<3466::aid-immu3466>3.0.co;2-9;
RA Kubin M.Z., Parshley D.L., Din W., Waugh J.Y., Davis-Smith T., Smith C.A.,
RA Macduff B.M., Armitage R.J., Chin W., Cassiano L., Borges L., Petersen M.,
RA Trinchieri G., Goodwin R.G.;
RT "Molecular cloning and biological characterization of NK cell activation-
RT inducing ligand, a counterstructure for CD48.";
RL Eur. J. Immunol. 29:3466-3477(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), PHOSPHORYLATION, AND INTERACTION
RP WITH SH2D1A AND PTPN11.
RX PubMed=10358138;
RA Tangye S.G., Lazetic S., Woollatt E., Sutherland G.R., Lanier L.L.,
RA Phillips J.H.;
RT "Human 2B4, an activating NK cell receptor, recruits the protein tyrosine
RT phosphatase SHP-2 and the adaptor signaling protein SAP.";
RL J. Immunol. 162:6981-6985(1999).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND INTERACTION WITH CD48.
RC TISSUE=Natural killer cell;
RX PubMed=10458320; DOI=10.1034/j.1399-0039.1999.540103.x;
RA Boles K.S., Nakajima H., Colonna M., Chuang S.S., Stepp S.E., Bennett M.,
RA Kumar V., Mathew P.A.;
RT "Molecular characterization of a novel human natural killer cell receptor
RT homologous to mouse 2B4.";
RL Tissue Antigens 54:27-34(1999).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=11003394; DOI=10.1007/s002510000237;
RA Kumaresan P.R., Mathew P.A.;
RT "Structure of the human natural killer cell receptor 2B4 gene and
RT identification of a novel alternative transcript.";
RL Immunogenetics 51:987-992(2000).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 3 AND 4), FUNCTION, AND INTERACTION
RP WITH INPP5D.
RC TISSUE=Lymphoid tissue;
RX PubMed=10934222; DOI=10.1084/jem.192.3.337;
RA Parolini S., Bottino C., Falco M., Augugliaro R., Giliani S.,
RA Franceschini R., Ochs H.D., Wolf H., Bonnefoy J.-Y., Biassoni R.,
RA Moretta L., Notarangelo L.D., Moretta A.;
RT "X-linked lymphoproliferative disease: 2B4 molecules displaying inhibitory
RT rather than activating function are responsible for the inability of
RT natural killer cells to kill Epstein-Barr virus-infected cells.";
RL J. Exp. Med. 192:337-346(2000).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RC TISSUE=Lymphoid tissue;
RA Biassoni R., Falco M.;
RT "Activating NK receptor homolog to the murine 2B4.";
RL Submitted (JUL-1999) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
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 [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 28-133.
RA Lennon G.P., Eccleston D.W., Pridgeon C., Pazmany L., Moots R.J.;
RL Submitted (MAR-2001) to the EMBL/GenBank/DDBJ databases.
RN [12]
RP PROTEIN SEQUENCE OF 22-36.
RX PubMed=15340161; DOI=10.1110/ps.04682504;
RA Zhang Z., Henzel W.J.;
RT "Signal peptide prediction based on analysis of experimentally verified
RT cleavage sites.";
RL Protein Sci. 13:2819-2824(2004).
RN [13]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=8376943; DOI=10.1084/jem.178.4.1397;
RA Valiante N.M., Trinchieri G.;
RT "Identification of a novel signal transduction surface molecule on human
RT cytotoxic lymphocytes.";
RL J. Exp. Med. 178:1397-1406(1993).
RN [14]
RP INTERACTION WITH CD48.
RX PubMed=9841922; DOI=10.1084/jem.188.11.2083;
RA Brown M.H., Boles K., van der Merwe P.A., Kumar V., Mathew P.A.,
RA Barclay A.N.;
RT "2B4, the natural killer and T cell immunoglobulin superfamily surface
RT protein, is a ligand for CD48.";
RL J. Exp. Med. 188:2083-2090(1998).
RN [15]
RP FUNCTION.
RX PubMed=10741393;
RX DOI=10.1002/1521-4141(200003)30:3<787::aid-immu787>3.0.co;2-i;
RA Sivori S., Parolini S., Falco M., Marcenaro E., Biassoni R., Bottino C.,
RA Moretta L., Moretta A.;
RT "2B4 functions as a co-receptor in human NK cell activation.";
RL Eur. J. Immunol. 30:787-793(2000).
RN [16]
RP PHOSPHORYLATION, AND SUBCELLULAR LOCATION.
RX PubMed=11034353; DOI=10.4049/jimmunol.165.7.3545;
RA Watzl C., Stebbins C.C., Long E.O.;
RT "NK cell inhibitory receptors prevent tyrosine phosphorylation of the
RT activation receptor 2B4 (CD244).";
RL J. Immunol. 165:3545-3548(2000).
RN [17]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=11714776; DOI=10.4049/jimmunol.167.11.6165;
RA Speiser D.E., Colonna M., Ayyoub M., Cella M., Pittet M.J., Batard P.,
RA Valmori D., Guillaume P., Lienard D., Cerottini J.C., Romero P.;
RT "The activatory receptor 2B4 is expressed in vivo by human CD8+ effector
RT alpha beta T cells.";
RL J. Immunol. 167:6165-6170(2001).
RN [18]
RP INTERACTION WITH PIK3R1.
RX PubMed=11815622; DOI=10.1074/jbc.m112029200;
RA Aoukaty A., Tan R.;
RT "Association of the X-linked lymphoproliferative disease gene product
RT SAP/SH2D1A with 2B4, a natural killer cell-activating molecule, is
RT dependent on phosphoinositide 3-kinase.";
RL J. Biol. Chem. 277:13331-13337(2002).
RN [19]
RP FUNCTION.
RX PubMed=11917118; DOI=10.1073/pnas.072065999;
RA Sivori S., Falco M., Marcenaro E., Parolini S., Biassoni R., Bottino C.,
RA Moretta L., Moretta A.;
RT "Early expression of triggering receptors and regulatory role of 2B4 in
RT human natural killer cell precursors undergoing in vitro differentiation.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:4526-4531(2002).
RN [20]
RP INTERACTION WITH SH2D1A; SH2D1B; INPP5D AND PTPN11, AND PHOSPHORYLATION AT
RP TYR-271; TYR-297; TYR-317 AND TYR-342.
RX PubMed=12458214; DOI=10.1074/jbc.m206649200;
RA Li C., Iosef C., Jia C.Y., Han V.K., Li S.S.;
RT "Dual functional roles for the X-linked lymphoproliferative syndrome gene
RT product SAP/SH2D1A in signaling through the signaling lymphocyte activation
RT molecule (SLAM) family of immune receptors.";
RL J. Biol. Chem. 278:3852-3859(2003).
RN [21]
RP FUNCTION, DOMAIN ITSM MOTIF, INTERACTION WITH INPP5D; PTPN11; PTPN6; CSK;
RP FYN AND SH2D1A, AND PHOSPHORYLATION AT TYR-271; TYR-297; TYR-317 AND
RP TYR-342.
RX PubMed=15713798; DOI=10.1182/blood-2004-09-3796;
RA Eissmann P., Beauchamp L., Wooters J., Tilton J.C., Long E.O., Watzl C.;
RT "Molecular basis for positive and negative signaling by the natural killer
RT cell receptor 2B4 (CD244).";
RL Blood 105:4722-4729(2005).
RN [22]
RP MUTAGENESIS OF LYS-68 AND GLU-70.
RX PubMed=16002700; DOI=10.4049/jimmunol.175.2.1005;
RA Mathew S.O., Kumaresan P.R., Lee J.K., Huynh V.T., Mathew P.A.;
RT "Mutational analysis of the human 2B4 (CD244)/CD48 interaction: Lys68 and
RT Glu70 in the V domain of 2B4 are critical for CD48 binding and functional
RT activation of NK cells.";
RL J. Immunol. 175:1005-1013(2005).
RN [23]
RP ALTERNATIVE SPLICING (ISOFORMS 1 AND 2).
RX PubMed=19499526; DOI=10.1002/eji.200838733;
RA Mathew S.O., Rao K.K., Kim J.R., Bambard N.D., Mathew P.A.;
RT "Functional role of human NK cell receptor 2B4 (CD244) isoforms.";
RL Eur. J. Immunol. 39:1632-1641(2009).
RN [24]
RP INTERACTION WITH MHC CLASS I PROTEINS.
RX PubMed=20164429; DOI=10.4049/jimmunol.0901572;
RA Betser-Cohen G., Mizrahi S., Elboim M., Alsheich-Bartok O., Mandelboim O.;
RT "The association of MHC class I proteins with the 2B4 receptor inhibits
RT self-killing of human NK cells.";
RL J. Immunol. 184:2761-2768(2010).
RN [25]
RP GLYCOSYLATION AT ASN-71; ASN-77 AND ASN-89.
RX PubMed=21606496; DOI=10.1074/jbc.m111.225334;
RA Margraf-Schonfeld S., Bohm C., Watzl C.;
RT "Glycosylation affects ligand binding and function of the activating
RT natural killer cell receptor 2B4 (CD244) protein.";
RL J. Biol. Chem. 286:24142-24149(2011).
RN [26]
RP INTERACTION WITH SH2D1A; SH2D1B AND INPP5D, AND DOMAIN ITSM MOTIF.
RX PubMed=24642916; DOI=10.1371/journal.pone.0092184;
RA Wilson T.J., Garner L.I., Metcalfe C., King E., Margraf S., Brown M.H.;
RT "Fine specificity and molecular competition in SLAM family receptor
RT signalling.";
RL PLoS ONE 9:E92184-E92184(2014).
RN [27]
RP INTERACTION WITH SH2D1A AND INPP5D, DOMAIN ITSM MOTIF, AND PHOSPHORYLATION
RP AT TYR-271 AND TYR-297.
RX PubMed=26221972; DOI=10.1111/imm.12513;
RA Margraf S., Garner L.I., Wilson T.J., Brown M.H.;
RT "A polymorphism in a phosphotyrosine signalling motif of CD229 (Ly9,
RT SLAMF3) alters SH2 domain binding and T-cell activation.";
RL Immunology 146:392-400(2015).
RN [28]
RP INTERACTION WITH CD48.
RX PubMed=27249817; DOI=10.1098/rsob.160010;
RA Claus M., Wingert S., Watzl C.;
RT "Modulation of natural killer cell functions by interactions between 2B4
RT and CD48 in cis and in trans.";
RL Open Biol. 6:0-0(2016).
CC -!- FUNCTION: Heterophilic receptor of the signaling lymphocytic activation
CC molecule (SLAM) family; its ligand is CD48. SLAM receptors triggered by
CC homo- or heterotypic cell-cell interactions are modulating the
CC activation and differentiation of a wide variety of immune cells and
CC thus are involved in the regulation and interconnection of both innate
CC and adaptive immune response. Activities are controlled by presence or
CC absence of small cytoplasmic adapter proteins, SH2D1A/SAP and/or
CC SH2D1B/EAT-2. Acts as activating natural killer (NK) cell receptor
CC (PubMed:10359122, PubMed:8376943, PubMed:11714776). Activating function
CC implicates association with SH2D1A and FYN (PubMed:15713798).
CC Downstreaming signaling involves predominantly VAV1, and, to a lesser
CC degree, INPP5D/SHIP1 and CBL. Signal attenuation in the absence of
CC SH2D1A is proposed to be dependent on INPP5D and to a lesser extent
CC PTPN6/SHP-1 and PTPN11/SHP-2 (PubMed:10934222, PubMed:15713798).
CC Stimulates NK cell cytotoxicity, production of IFN-gamma and granule
CC exocytosis (PubMed:8376943, PubMed:11714776). Optimal expansion and
CC activation of NK cells seems to be dependent on the engagement of CD244
CC with CD48 expressed on neighboring NK cells (By similarity). Acts as
CC costimulator in NK activation by enhancing signals by other NK
CC receptors such as NCR3 and NCR1 (PubMed:10741393). At early stages of
CC NK cell differentiation may function as an inhibitory receptor possibly
CC ensuring the self-tolerance of developing NK cells (PubMed:11917118).
CC Involved in the regulation of CD8(+) T-cell proliferation; expression
CC on activated T-cells and binding to CD488 provides costimulatory-like
CC function for neighboring T-cells (By similarity). Inhibits inflammatory
CC responses in dendritic cells (DCs) (By similarity).
CC {ECO:0000250|UniProtKB:Q07763, ECO:0000269|PubMed:10359122,
CC ECO:0000269|PubMed:10741393, ECO:0000269|PubMed:10934222,
CC ECO:0000269|PubMed:11714776, ECO:0000269|PubMed:11917118,
CC ECO:0000269|PubMed:8376943, ECO:0000305|PubMed:15713798}.
CC -!- SUBUNIT: Interacts with CD48 (PubMed:9841922,PubMed:27249817).
CC Interacts (via phosphorylated ITSM 1-4) with SH2D1A (via SH2 domain);
CC SH2D1A probably mediates association with FYN. Interacts (via
CC phosphorylated ITSM 3) with PTPN11/SHP-2, INPP5D/SHIP1, PTPN6/SHP-1 and
CC CSK; binding of SH2D1A/SAP prevents association with PTPN11, PTPN6 and
CC CSK; conflictingly a similar association has been described for
CC phosphorylated ITSM 1 also including GRB2 and PLCG1. Interacts weakly
CC (via phosphorylated ITSM 2) with PTPN11/SHP-2 and CSK (PubMed:10358138,
CC PubMed:10934222, PubMed:12458214, PubMed:24642916, PubMed:26221972,
CC PubMed:15713798). Interacts with SH2D1B (PubMed:12458214,
CC PubMed:24642916). Interacts with PIK3R1; PI3K recruits SH2D1A
CC (PubMed:11815622). Interacts with MHC class I proteins; the interaction
CC is proposed to prevent self-killing of NK cells.
CC {ECO:0000250|UniProtKB:Q07763, ECO:0000269|PubMed:10358138,
CC ECO:0000269|PubMed:10359122, ECO:0000269|PubMed:10458320,
CC ECO:0000269|PubMed:10556801, ECO:0000269|PubMed:10934222,
CC ECO:0000269|PubMed:11815622, ECO:0000269|PubMed:12458214,
CC ECO:0000269|PubMed:15713798, ECO:0000269|PubMed:20164429,
CC ECO:0000269|PubMed:24642916, ECO:0000269|PubMed:26221972,
CC ECO:0000269|PubMed:27249817, ECO:0000269|PubMed:9841922}.
CC -!- INTERACTION:
CC Q9BZW8; P61769: B2M; NbExp=2; IntAct=EBI-1580565, EBI-714718;
CC Q9BZW8; P09326: CD48; NbExp=4; IntAct=EBI-1580565, EBI-714770;
CC Q9BZW8; Q92835: INPP5D; NbExp=6; IntAct=EBI-1580565, EBI-1380477;
CC Q9BZW8; P19174: PLCG1; NbExp=2; IntAct=EBI-1580565, EBI-79387;
CC Q9BZW8; Q06124: PTPN11; NbExp=5; IntAct=EBI-1580565, EBI-297779;
CC Q9BZW8; P29350: PTPN6; NbExp=2; IntAct=EBI-1580565, EBI-78260;
CC Q9BZW8; O60880: SH2D1A; NbExp=10; IntAct=EBI-1580565, EBI-6983382;
CC Q9BZW8; O60880-1: SH2D1A; NbExp=2; IntAct=EBI-1580565, EBI-15552052;
CC Q9BZW8; O14796: SH2D1B; NbExp=7; IntAct=EBI-1580565, EBI-3923013;
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000305}; Single-pass type I
CC membrane protein {ECO:0000305}. Cell membrane {ECO:0000305}.
CC Note=Receptor engagement results in a recruitment to lipid drafts
CC essential for the subsequent tyrosine phosphorylation of the ITSMs.
CC {ECO:0000269|PubMed:11034353}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1; Synonyms=H2B4-B;
CC IsoId=Q9BZW8-1; Sequence=Displayed;
CC Name=2; Synonyms=H2B4-A;
CC IsoId=Q9BZW8-2; Sequence=VSP_010397;
CC Name=3; Synonyms=H2B4;
CC IsoId=Q9BZW8-3; Sequence=VSP_010397, VSP_010399, VSP_010400;
CC Name=4; Synonyms=H2B4b;
CC IsoId=Q9BZW8-4; Sequence=VSP_010398;
CC -!- TISSUE SPECIFICITY: Expressed in spleen, PBL, followed by lung, liver,
CC testis and small intestine. Expressed in all natural killer (NK) cells,
CC monocytes and basophils, TCR-gamma/delta+ T-cells, monocytes,
CC basophils, and on a subset of CD8(+) T-cells.
CC {ECO:0000269|PubMed:10556801, ECO:0000269|PubMed:11714776,
CC ECO:0000269|PubMed:8376943}.
CC -!- DOMAIN: The ITSMs (immunoreceptor tyrosine-based switch motifs) with
CC the consensus sequence T-X-Y-X-X-[VI] present in SLAM family receptors
CC have overlapping specificity for activating and inhibitory SH2 domain-
CC containing binding partners. Especially they mediate the interaction
CC with the SH2 domain of SH2D1A and SH2D1B. A 'three-pronged' mechanism
CC is proposed involving threonine (position -2), phosphorylated tyrosine
CC (position 0) and valine/isoleucine (position +3).
CC {ECO:0000250|UniProtKB:Q13291, ECO:0000269|PubMed:15713798,
CC ECO:0000269|PubMed:26221972}.
CC -!- PTM: N-linked glycosylation is essential for the binding to its ligand
CC CD48. Also O-glycosylated, in contrast, O-linked sialylation has a
CC negative impact on ligand binding. {ECO:0000269|PubMed:21606496}.
CC -!- PTM: Phosphorylated by FYN and CSK on tyrosine residues following
CC activation. Coligation with inhibitory receptors such as KIR2DL1
CC inhibits phosphorylation upon contact of NK cells with sensitive target
CC cells. {ECO:0000269|PubMed:10358138, ECO:0000269|PubMed:11034353}.
CC -!- MISCELLANEOUS: [Isoform 2]: Binds to CD48 with a sronger affinity than
CC isoform 1, and interactions induces greater cytotoxicity and
CC intracellular calcium release. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AF105261; AAD32538.1; -; mRNA.
DR EMBL; AF117711; AAF28833.1; -; mRNA.
DR EMBL; AF145782; AAD38951.1; -; mRNA.
DR EMBL; AF107761; AAD37838.1; -; mRNA.
DR EMBL; AF242540; AAK00233.1; -; mRNA.
DR EMBL; AJ245376; CAC00648.1; -; mRNA.
DR EMBL; AJ245377; CAC00649.1; -; mRNA.
DR EMBL; AJ245375; CAC00647.1; -; mRNA.
DR EMBL; AL354714; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471121; EAW52691.1; -; Genomic_DNA.
DR EMBL; CH471121; EAW52692.1; -; Genomic_DNA.
DR EMBL; CH471121; EAW52693.1; -; Genomic_DNA.
DR EMBL; BC028073; AAH28073.1; -; mRNA.
DR EMBL; BC053985; AAH53985.1; -; mRNA.
DR EMBL; AF363452; AAK50015.1; -; mRNA.
DR CCDS; CCDS1210.1; -. [Q9BZW8-2]
DR CCDS; CCDS53398.1; -. [Q9BZW8-4]
DR CCDS; CCDS53399.1; -. [Q9BZW8-1]
DR RefSeq; NP_001160135.1; NM_001166663.1. [Q9BZW8-1]
DR RefSeq; NP_001160136.1; NM_001166664.1. [Q9BZW8-4]
DR RefSeq; NP_057466.1; NM_016382.3. [Q9BZW8-2]
DR RefSeq; XP_011507924.1; XM_011509622.2. [Q9BZW8-3]
DR AlphaFoldDB; Q9BZW8; -.
DR SMR; Q9BZW8; -.
DR BioGRID; 119709; 39.
DR DIP; DIP-40331N; -.
DR ELM; Q9BZW8; -.
DR IntAct; Q9BZW8; 34.
DR MINT; Q9BZW8; -.
DR STRING; 9606.ENSP00000357012; -.
DR GlyGen; Q9BZW8; 8 sites.
DR iPTMnet; Q9BZW8; -.
DR PhosphoSitePlus; Q9BZW8; -.
DR BioMuta; CD244; -.
DR DMDM; 47605541; -.
DR jPOST; Q9BZW8; -.
DR MassIVE; Q9BZW8; -.
DR PaxDb; Q9BZW8; -.
DR PeptideAtlas; Q9BZW8; -.
DR PRIDE; Q9BZW8; -.
DR ProteomicsDB; 79913; -. [Q9BZW8-1]
DR ProteomicsDB; 79914; -. [Q9BZW8-2]
DR ProteomicsDB; 79915; -. [Q9BZW8-3]
DR ProteomicsDB; 79916; -. [Q9BZW8-4]
DR Antibodypedia; 2392; 831 antibodies from 42 providers.
DR DNASU; 51744; -.
DR Ensembl; ENST00000322302.7; ENSP00000313619.7; ENSG00000122223.13. [Q9BZW8-4]
DR Ensembl; ENST00000368033.7; ENSP00000357012.3; ENSG00000122223.13. [Q9BZW8-1]
DR Ensembl; ENST00000368034.9; ENSP00000357013.4; ENSG00000122223.13. [Q9BZW8-2]
DR Ensembl; ENST00000492063.5; ENSP00000432636.1; ENSG00000122223.13. [Q9BZW8-3]
DR GeneID; 51744; -.
DR KEGG; hsa:51744; -.
DR MANE-Select; ENST00000368034.9; ENSP00000357013.4; NM_016382.4; NP_057466.1. [Q9BZW8-2]
DR UCSC; uc001fxa.4; human. [Q9BZW8-1]
DR CTD; 51744; -.
DR DisGeNET; 51744; -.
DR GeneCards; CD244; -.
DR HGNC; HGNC:18171; CD244.
DR HPA; ENSG00000122223; Tissue enhanced (bone marrow, lymphoid tissue).
DR MalaCards; CD244; -.
DR MIM; 605554; gene.
DR neXtProt; NX_Q9BZW8; -.
DR OpenTargets; ENSG00000122223; -.
DR PharmGKB; PA134905192; -.
DR VEuPathDB; HostDB:ENSG00000122223; -.
DR eggNOG; ENOG502S7N7; Eukaryota.
DR GeneTree; ENSGT01030000234540; -.
DR HOGENOM; CLU_065827_0_0_1; -.
DR InParanoid; Q9BZW8; -.
DR OMA; TCFCVWR; -.
DR OrthoDB; 1532935at2759; -.
DR PhylomeDB; Q9BZW8; -.
DR TreeFam; TF334964; -.
DR PathwayCommons; Q9BZW8; -.
DR Reactome; R-HSA-202733; Cell surface interactions at the vascular wall.
DR SignaLink; Q9BZW8; -.
DR BioGRID-ORCS; 51744; 15 hits in 1059 CRISPR screens.
DR GeneWiki; CD244; -.
DR GenomeRNAi; 51744; -.
DR Pharos; Q9BZW8; Tbio.
DR PRO; PR:Q9BZW8; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; Q9BZW8; protein.
DR Bgee; ENSG00000122223; Expressed in granulocyte and 105 other tissues.
DR Genevisible; Q9BZW8; HS.
DR GO; GO:0009897; C:external side of plasma membrane; IDA:MGI.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0042288; F:MHC class I protein binding; IDA:UniProtKB.
DR GO; GO:0038023; F:signaling receptor activity; TAS:ProtInc.
DR GO; GO:0002250; P:adaptive immune response; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0002323; P:natural killer cell activation involved in immune response; IDA:UniProtKB.
DR GO; GO:0071663; P:positive regulation of granzyme B production; IDA:UniProtKB.
DR GO; GO:0060732; P:positive regulation of inositol phosphate biosynthetic process; IDA:UniProtKB.
DR GO; GO:0032729; P:positive regulation of interferon-gamma production; IDA:UniProtKB.
DR GO; GO:0032757; P:positive regulation of interleukin-8 production; IDA:UniProtKB.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR Gene3D; 2.60.40.10; -; 2.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR036179; Ig-like_dom_sf.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR024304; NK_rcpt_2B4.
DR InterPro; IPR024303; NK_rcpt_2B4_Ig_dom.
DR PANTHER; PTHR12080:SF56; PTHR12080:SF56; 1.
DR Pfam; PF13895; Ig_2; 1.
DR Pfam; PF11465; Receptor_2B4; 1.
DR SUPFAM; SSF48726; SSF48726; 2.
DR PROSITE; PS50835; IG_LIKE; 1.
PE 1: Evidence at protein level;
KW Adaptive immunity; Alternative splicing; Cell membrane;
KW Direct protein sequencing; Disulfide bond; Glycoprotein; Immunity;
KW Immunoglobulin domain; Innate immunity; Membrane; Phosphoprotein; Receptor;
KW Reference proteome; Repeat; Signal; Transmembrane; Transmembrane helix.
FT SIGNAL 1..21
FT /evidence="ECO:0000269|PubMed:10556801,
FT ECO:0000269|PubMed:15340161"
FT CHAIN 22..370
FT /note="Natural killer cell receptor 2B4"
FT /id="PRO_0000014668"
FT TOPO_DOM 22..229
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 230..250
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 251..370
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 22..127
FT /note="Ig-like 1"
FT DOMAIN 131..215
FT /note="Ig-like 2"
FT REGION 324..370
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 269..274
FT /note="ITSM 1"
FT /evidence="ECO:0000250|UniProtKB:Q13291"
FT MOTIF 295..300
FT /note="ITSM 2"
FT /evidence="ECO:0000250|UniProtKB:Q13291"
FT MOTIF 315..320
FT /note="ITSM 3"
FT /evidence="ECO:0000250|UniProtKB:Q13291"
FT MOTIF 340..345
FT /note="ITSM 4"
FT /evidence="ECO:0000250|UniProtKB:Q13291"
FT COMPBIAS 332..355
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 271
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000305|PubMed:12458214,
FT ECO:0000305|PubMed:15713798, ECO:0000305|PubMed:26221972"
FT MOD_RES 297
FT /note="Phosphotyrosine; by FYN"
FT /evidence="ECO:0000305|PubMed:12458214,
FT ECO:0000305|PubMed:15713798, ECO:0000305|PubMed:26221972"
FT MOD_RES 317
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000305|PubMed:12458214,
FT ECO:0000305|PubMed:15713798"
FT MOD_RES 342
FT /note="Phosphotyrosine; by FYN"
FT /evidence="ECO:0000305|PubMed:12458214,
FT ECO:0000305|PubMed:15713798"
FT CARBOHYD 71
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:21606496"
FT CARBOHYD 77
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:21606496"
FT CARBOHYD 89
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:21606496"
FT CARBOHYD 164
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 181
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 192
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 200
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 213
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 157..199
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT VAR_SEQ 127..131
FT /note="Missing (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:10358138,
FT ECO:0000303|PubMed:10359122, ECO:0000303|PubMed:10458320,
FT ECO:0000303|PubMed:10556801, ECO:0000303|PubMed:10934222,
FT ECO:0000303|PubMed:15489334, ECO:0000303|Ref.7"
FT /id="VSP_010397"
FT VAR_SEQ 128..224
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:10934222"
FT /id="VSP_010398"
FT VAR_SEQ 326..334
FT /note="SGSRKRNHS -> GDRFYSFSG (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:10934222"
FT /id="VSP_010399"
FT VAR_SEQ 335..370
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:10934222"
FT /id="VSP_010400"
FT VARIANT 89
FT /note="N -> D (in dbSNP:rs34846692)"
FT /id="VAR_056036"
FT VARIANT 323
FT /note="S -> F (in dbSNP:rs12064925)"
FT /id="VAR_056037"
FT MUTAGEN 68
FT /note="K->A: Disrupts interaction with CD48; when
FT associated with A-70."
FT /evidence="ECO:0000269|PubMed:16002700"
FT MUTAGEN 70
FT /note="E->A: Disrupts interaction with CD48; when
FT associated with A-68."
FT /evidence="ECO:0000269|PubMed:16002700"
FT CONFLICT 127..133
FT /note="ESLLPDK -> GMAMCPM (in Ref. 10; AAK50015)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 370 AA; 41616 MW; 959FF8DBB0BACC87 CRC64;
MLGQVVTLIL LLLLKVYQGK GCQGSADHVV SISGVPLQLQ PNSIQTKVDS IAWKKLLPSQ
NGFHHILKWE NGSLPSNTSN DRFSFIVKNL SLLIKAAQQQ DSGLYCLEVT SISGKVQTAT
FQVFVFESLL PDKVEKPRLQ GQGKILDRGR CQVALSCLVS RDGNVSYAWY RGSKLIQTAG
NLTYLDEEVD INGTHTYTCN VSNPVSWESH TLNLTQDCQN AHQEFRFWPF LVIIVILSAL
FLGTLACFCV WRRKRKEKQS ETSPKEFLTI YEDVKDLKTR RNHEQEQTFP GGGSTIYSMI
QSQSSAPTSQ EPAYTLYSLI QPSRKSGSRK RNHSPSFNST IYEVIGKSQP KAQNPARLSR
KELENFDVYS
