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Protein

Natural killer cell receptor 2B4

Gene

CD244

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Heterophilic receptor of the signaling lymphocytic activation molecule (SLAM) family; its ligand is CD48. SLAM receptors triggered by homo- or heterotypic cell-cell interactions are modulating the activation and differentiation of a wide variety of immune cells and thus are involved in the regulation and interconnection of both innate and adaptive immune response. Activities are controlled by presence or absence of small cytoplasmic adapter proteins, SH2D1A/SAP and/or SH2D1B/EAT-2. Acts as activating natural killer (NK) cell receptor (PubMed:10359122, PubMed:8376943, PubMed:11714776). Activating function implicates association with SH2D1A and FYN (PubMed:15713798). Downstreaming signaling involves predominantly VAV1, and, to a lesser degree, INPP5D/SHIP1 and CBL. Signal attenuation in the absence of SH2D1A is proposed to be dependent on INPP5D and to a lesser extent PTPN6/SHP-1 and PTPN11/SHP-2 (PubMed:10934222, PubMed:15713798). Stimulates NK cell cytotoxicity, production of IFN-gamma and granule exocytosis (PubMed:8376943, PubMed:11714776). Optimal expansion and activation of NK cells seems to be dependent on the engagement of CD244 with CD48 expressed on neighboring NK cells (By similarity). Acts as costimulator in NK activation by enhancing signals by other NK receptors such as NCR3 and NCR1 (PubMed:10741393). At early stages of NK cell differentiation may function as an inhibitory receptor possibly ensuring the self-tolerance of developing NK cells (PubMed:11917118). Involved in the regulation of CD8+ T-cell proliferation; expression on activated T-cells and binding to CD488 provides costimulatory-like function for neighboring T-cells (By similarity). Inhibits inflammatory responses in dendritic cells (DCs) (By similarity).By similarity1 Publication6 Publications

GO - Molecular functioni

  • MHC class I protein binding Source: UniProtKB
  • receptor activity Source: ProtInc

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Receptor

Keywords - Biological processi

Adaptive immunity, Immunity, Innate immunity

Enzyme and pathway databases

ReactomeiR-HSA-202733. Cell surface interactions at the vascular wall.
SignaLinkiQ9BZW8.

Names & Taxonomyi

Protein namesi
Recommended name:
Natural killer cell receptor 2B4
Alternative name(s):
NK cell activation-inducing ligand
Short name:
NAIL
NK cell type I receptor protein 2B4
Short name:
NKR2B4
Short name:
h2B4
SLAM family member 4
Short name:
SLAMF4
Signaling lymphocytic activation molecule 4
CD_antigen: CD244
Gene namesi
Name:CD244
Synonyms:2B4
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

HGNCiHGNC:18171. CD244.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini22 – 229ExtracellularSequence analysisAdd BLAST208
Transmembranei230 – 250HelicalSequence analysisAdd BLAST21
Topological domaini251 – 370CytoplasmicSequence analysisAdd BLAST120

GO - Cellular componenti

  • external side of plasma membrane Source: MGI
  • integral component of membrane Source: UniProtKB-KW
  • plasma membrane Source: Reactome
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi68K → A: Disrupts interaction with CD48; when associated with A-70. 1 Publication1
Mutagenesisi70E → A: Disrupts interaction with CD48; when associated with A-68. 1 Publication1

Organism-specific databases

DisGeNETi51744.
MalaCardsiCD244.
OpenTargetsiENSG00000122223.
PharmGKBiPA134905192.

Polymorphism and mutation databases

BioMutaiCD244.
DMDMi47605541.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 212 PublicationsAdd BLAST21
ChainiPRO_000001466822 – 370Natural killer cell receptor 2B4Add BLAST349

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi71N-linked (GlcNAc...)1 Publication1
Glycosylationi77N-linked (GlcNAc...)1 Publication1
Glycosylationi89N-linked (GlcNAc...)1 Publication1
Disulfide bondi157 ↔ 199PROSITE-ProRule annotation
Glycosylationi164N-linked (GlcNAc...)Sequence analysis1
Glycosylationi181N-linked (GlcNAc...)Sequence analysis1
Glycosylationi192N-linked (GlcNAc...)Sequence analysis1
Glycosylationi200N-linked (GlcNAc...)Sequence analysis1
Glycosylationi213N-linked (GlcNAc...)Sequence analysis1
Modified residuei271Phosphotyrosine3 Publications1
Modified residuei297Phosphotyrosine; by FYN3 Publications1
Modified residuei317Phosphotyrosine2 Publications1
Modified residuei342Phosphotyrosine; by FYN2 Publications1

Post-translational modificationi

N-linked glycosylation is essential for the binding to its ligand CD48. Also O-glycosylated, in contrast, O-linked sialylation has a negative impact on ligand binding.1 Publication
Phosphorylated by FYN and CSK on tyrosine residues following activation. Coligation with inhibitory receptors such as KIR2DL1 inhibits phosphorylation upon contact of NK cells with sensitive target cells.2 Publications

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein

Proteomic databases

PaxDbiQ9BZW8.
PeptideAtlasiQ9BZW8.
PRIDEiQ9BZW8.

PTM databases

iPTMnetiQ9BZW8.
PhosphoSitePlusiQ9BZW8.

Expressioni

Tissue specificityi

Expressed in spleen, PBL, followed by lung, liver, testis and small intestine. Expressed in all natural killer (NK) cells, monocytes and basophils, TCR-gamma/delta+ T-cells, monocytes, basophils, and on a subset of CD8+ T-cells.3 Publications

Gene expression databases

BgeeiENSG00000122223.
CleanExiHS_CD244.
GenevisibleiQ9BZW8. HS.

Organism-specific databases

HPAiHPA010628.

Interactioni

Subunit structurei

Interacts with CD48 (PubMed:9841922). Interacts (via phosphorylated ITSM 1-4) with SH2D1A (via SH2 domain); SH2D1A probably mediates association with FYN. Interacts (via phosphorylated ITSM 3) with PTPN11/SHP-2, INPP5D/SHIP1, PTPN6/SHP-1 and CSK; binding of SH2D1A/SAP prevents association with PTPN11, PTPN6 and CSK; conflictingly a similar association has been described for phosphorylated ITSM 1 also including GRB2 and PLCG1. Interacts weakly (via phosphorylated ITSM 2) with PTPN11/SHP-2 and CSK (PubMed:10358138, PubMed:10934222, PubMed:12458214, PubMed:24642916, PubMed:26221972, PubMed:15713798). Interacts with SH2D1B (PubMed:12458214, PubMed:24642916). Interacts with PIK3R1; PI3K recruits SH2D1A (PubMed:11815622). Interacts with MHC class I proteins; the interaction is proposed to prevent self-killing of NK cells.By similarity12 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
CD48P093263EBI-1580565,EBI-714770
INPP5DQ928356EBI-1580565,EBI-1380477
PLCG1P191742EBI-1580565,EBI-79387
PTPN11Q061245EBI-1580565,EBI-297779
SH2D1AO608807EBI-1580565,EBI-6983382
SH2D1BO147965EBI-1580565,EBI-3923013

GO - Molecular functioni

  • MHC class I protein binding Source: UniProtKB

Protein-protein interaction databases

BioGridi119709. 24 interactors.
DIPiDIP-40331N.
IntActiQ9BZW8. 13 interactors.
MINTiMINT-3371787.
STRINGi9606.ENSP00000357012.

Structurei

3D structure databases

ProteinModelPortaliQ9BZW8.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini22 – 127Ig-like 1Add BLAST106
Domaini131 – 215Ig-like 2Add BLAST85

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi269 – 274ITSM 1By similarity6
Motifi295 – 300ITSM 2By similarity6
Motifi315 – 320ITSM 3By similarity6
Motifi340 – 345ITSM 4By similarity6

Domaini

The ITSMs (immunoreceptor tyrosine-based switch motifs) with the consensus sequence T-X-Y-X-X-[VI] present in SLAM family receptors have overlapping specificity for activating and inhibitory SH2 domain-containing binding partners. Especially they mediate the interaction with the SH2 domain of SH2D1A and SH2D1B. A 'three-pronged' mechanism is proposed involving threonine (position -2), phosphorylated tyrosine (position 0) and valine/isoleucine (position +3).By similarity2 Publications

Sequence similaritiesi

Keywords - Domaini

Immunoglobulin domain, Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiENOG410IKYZ. Eukaryota.
ENOG410Y74Q. LUCA.
GeneTreeiENSGT00510000049238.
HOVERGENiHBG050850.
InParanoidiQ9BZW8.
KOiK06582.
OMAiTIYEDVK.
OrthoDBiEOG091G0DZW.
PhylomeDBiQ9BZW8.
TreeFamiTF334964.

Family and domain databases

Gene3Di2.60.40.10. 2 hits.
InterProiIPR007110. Ig-like_dom.
IPR013783. Ig-like_fold.
IPR024304. NK_rcpt_2B4.
IPR024303. NK_rcpt_2B4_Ig_dom.
[Graphical view]
PANTHERiPTHR12080:SF56. PTHR12080:SF56. 1 hit.
PfamiPF13895. Ig_2. 1 hit.
PF11465. Receptor_2B4. 1 hit.
[Graphical view]
SUPFAMiSSF48726. SSF48726. 2 hits.
PROSITEiPS50835. IG_LIKE. 1 hit.
[Graphical view]

Sequences (4)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 4 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q9BZW8-1) [UniParc]FASTAAdd to basket
Also known as: H2B4-B

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MLGQVVTLIL LLLLKVYQGK GCQGSADHVV SISGVPLQLQ PNSIQTKVDS
60 70 80 90 100
IAWKKLLPSQ NGFHHILKWE NGSLPSNTSN DRFSFIVKNL SLLIKAAQQQ
110 120 130 140 150
DSGLYCLEVT SISGKVQTAT FQVFVFESLL PDKVEKPRLQ GQGKILDRGR
160 170 180 190 200
CQVALSCLVS RDGNVSYAWY RGSKLIQTAG NLTYLDEEVD INGTHTYTCN
210 220 230 240 250
VSNPVSWESH TLNLTQDCQN AHQEFRFWPF LVIIVILSAL FLGTLACFCV
260 270 280 290 300
WRRKRKEKQS ETSPKEFLTI YEDVKDLKTR RNHEQEQTFP GGGSTIYSMI
310 320 330 340 350
QSQSSAPTSQ EPAYTLYSLI QPSRKSGSRK RNHSPSFNST IYEVIGKSQP
360 370
KAQNPARLSR KELENFDVYS
Length:370
Mass (Da):41,616
Last modified:May 24, 2004 - v2
Checksum:i959FF8DBB0BACC87
GO
Isoform 2 (identifier: Q9BZW8-2) [UniParc]FASTAAdd to basket
Also known as: H2B4-A

The sequence of this isoform differs from the canonical sequence as follows:
     127-131: Missing.

Note: Binds to CD48 with a sronger affinity than isoform 1, and interactions induces greater cytotoxicity and intracellular calcium release.
Show »
Length:365
Mass (Da):41,077
Checksum:i7DEDD0EBF2E19322
GO
Isoform 3 (identifier: Q9BZW8-3) [UniParc]FASTAAdd to basket
Also known as: H2B4

The sequence of this isoform differs from the canonical sequence as follows:
     127-131: Missing.
     326-334: SGSRKRNHS → GDRFYSFSG
     335-370: Missing.

Note: No experimental confirmation available.
Show »
Length:329
Mass (Da):36,987
Checksum:i639FE10EA76F074E
GO
Isoform 4 (identifier: Q9BZW8-4) [UniParc]FASTAAdd to basket
Also known as: H2B4b

The sequence of this isoform differs from the canonical sequence as follows:
     128-224: Missing.

Note: No experimental confirmation available.
Show »
Length:273
Mass (Da):30,784
Checksum:i036514F046E2099C
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti127 – 133ESLLPDK → GMAMCPM in AAK50015 (PubMed:15489334).Curated7

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_05603689N → D.Corresponds to variant rs34846692dbSNPEnsembl.1
Natural variantiVAR_056037323S → F.Corresponds to variant rs12064925dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_010397127 – 131Missing in isoform 2 and isoform 3. 7 Publications5
Alternative sequenceiVSP_010398128 – 224Missing in isoform 4. 1 PublicationAdd BLAST97
Alternative sequenceiVSP_010399326 – 334SGSRKRNHS → GDRFYSFSG in isoform 3. 1 Publication9
Alternative sequenceiVSP_010400335 – 370Missing in isoform 3. 1 PublicationAdd BLAST36

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF105261 mRNA. Translation: AAD32538.1.
AF117711 mRNA. Translation: AAF28833.1.
AF145782 mRNA. Translation: AAD38951.1.
AF107761 mRNA. Translation: AAD37838.1.
AF242540 mRNA. Translation: AAK00233.1.
AJ245376 mRNA. Translation: CAC00648.1.
AJ245377 mRNA. Translation: CAC00649.1.
AJ245375 mRNA. Translation: CAC00647.1.
AL354714 Genomic DNA. Translation: CAH72353.1.
AL354714 Genomic DNA. Translation: CAH72354.1.
AL354714 Genomic DNA. Translation: CAH72355.1.
CH471121 Genomic DNA. Translation: EAW52691.1.
CH471121 Genomic DNA. Translation: EAW52692.1.
CH471121 Genomic DNA. Translation: EAW52693.1.
BC028073 mRNA. Translation: AAH28073.1.
BC053985 mRNA. Translation: AAH53985.1.
AF363452 mRNA. Translation: AAK50015.1.
CCDSiCCDS1210.1. [Q9BZW8-2]
CCDS53398.1. [Q9BZW8-4]
CCDS53399.1. [Q9BZW8-1]
RefSeqiNP_001160135.1. NM_001166663.1. [Q9BZW8-1]
NP_001160136.1. NM_001166664.1. [Q9BZW8-4]
NP_057466.1. NM_016382.3. [Q9BZW8-2]
XP_011507924.1. XM_011509622.2. [Q9BZW8-3]
UniGeneiHs.157872.

Genome annotation databases

EnsembliENST00000322302; ENSP00000313619; ENSG00000122223. [Q9BZW8-4]
ENST00000368033; ENSP00000357012; ENSG00000122223. [Q9BZW8-1]
ENST00000368034; ENSP00000357013; ENSG00000122223. [Q9BZW8-2]
ENST00000492063; ENSP00000432636; ENSG00000122223. [Q9BZW8-3]
GeneIDi51744.
KEGGihsa:51744.
UCSCiuc001fxa.4. human. [Q9BZW8-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF105261 mRNA. Translation: AAD32538.1.
AF117711 mRNA. Translation: AAF28833.1.
AF145782 mRNA. Translation: AAD38951.1.
AF107761 mRNA. Translation: AAD37838.1.
AF242540 mRNA. Translation: AAK00233.1.
AJ245376 mRNA. Translation: CAC00648.1.
AJ245377 mRNA. Translation: CAC00649.1.
AJ245375 mRNA. Translation: CAC00647.1.
AL354714 Genomic DNA. Translation: CAH72353.1.
AL354714 Genomic DNA. Translation: CAH72354.1.
AL354714 Genomic DNA. Translation: CAH72355.1.
CH471121 Genomic DNA. Translation: EAW52691.1.
CH471121 Genomic DNA. Translation: EAW52692.1.
CH471121 Genomic DNA. Translation: EAW52693.1.
BC028073 mRNA. Translation: AAH28073.1.
BC053985 mRNA. Translation: AAH53985.1.
AF363452 mRNA. Translation: AAK50015.1.
CCDSiCCDS1210.1. [Q9BZW8-2]
CCDS53398.1. [Q9BZW8-4]
CCDS53399.1. [Q9BZW8-1]
RefSeqiNP_001160135.1. NM_001166663.1. [Q9BZW8-1]
NP_001160136.1. NM_001166664.1. [Q9BZW8-4]
NP_057466.1. NM_016382.3. [Q9BZW8-2]
XP_011507924.1. XM_011509622.2. [Q9BZW8-3]
UniGeneiHs.157872.

3D structure databases

ProteinModelPortaliQ9BZW8.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi119709. 24 interactors.
DIPiDIP-40331N.
IntActiQ9BZW8. 13 interactors.
MINTiMINT-3371787.
STRINGi9606.ENSP00000357012.

PTM databases

iPTMnetiQ9BZW8.
PhosphoSitePlusiQ9BZW8.

Polymorphism and mutation databases

BioMutaiCD244.
DMDMi47605541.

Proteomic databases

PaxDbiQ9BZW8.
PeptideAtlasiQ9BZW8.
PRIDEiQ9BZW8.

Protocols and materials databases

DNASUi51744.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000322302; ENSP00000313619; ENSG00000122223. [Q9BZW8-4]
ENST00000368033; ENSP00000357012; ENSG00000122223. [Q9BZW8-1]
ENST00000368034; ENSP00000357013; ENSG00000122223. [Q9BZW8-2]
ENST00000492063; ENSP00000432636; ENSG00000122223. [Q9BZW8-3]
GeneIDi51744.
KEGGihsa:51744.
UCSCiuc001fxa.4. human. [Q9BZW8-1]

Organism-specific databases

CTDi51744.
DisGeNETi51744.
GeneCardsiCD244.
HGNCiHGNC:18171. CD244.
HPAiHPA010628.
MalaCardsiCD244.
MIMi605554. gene.
neXtProtiNX_Q9BZW8.
OpenTargetsiENSG00000122223.
PharmGKBiPA134905192.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410IKYZ. Eukaryota.
ENOG410Y74Q. LUCA.
GeneTreeiENSGT00510000049238.
HOVERGENiHBG050850.
InParanoidiQ9BZW8.
KOiK06582.
OMAiTIYEDVK.
OrthoDBiEOG091G0DZW.
PhylomeDBiQ9BZW8.
TreeFamiTF334964.

Enzyme and pathway databases

ReactomeiR-HSA-202733. Cell surface interactions at the vascular wall.
SignaLinkiQ9BZW8.

Miscellaneous databases

ChiTaRSiCD244. human.
GeneWikiiCD244.
GenomeRNAii51744.
PROiQ9BZW8.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000122223.
CleanExiHS_CD244.
GenevisibleiQ9BZW8. HS.

Family and domain databases

Gene3Di2.60.40.10. 2 hits.
InterProiIPR007110. Ig-like_dom.
IPR013783. Ig-like_fold.
IPR024304. NK_rcpt_2B4.
IPR024303. NK_rcpt_2B4_Ig_dom.
[Graphical view]
PANTHERiPTHR12080:SF56. PTHR12080:SF56. 1 hit.
PfamiPF13895. Ig_2. 1 hit.
PF11465. Receptor_2B4. 1 hit.
[Graphical view]
SUPFAMiSSF48726. SSF48726. 2 hits.
PROSITEiPS50835. IG_LIKE. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiCD244_HUMAN
AccessioniPrimary (citable) accession number: Q9BZW8
Secondary accession number(s): Q5VYI2
, Q5VYI6, Q5VYI7, Q96T47, Q9NQD2, Q9NQD3, Q9Y288
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 24, 2004
Last sequence update: May 24, 2004
Last modified: November 2, 2016
This is version 141 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human cell differentiation molecules
    CD nomenclature of surface proteins of human leucocytes and list of entries
  2. Human chromosome 1
    Human chromosome 1: entries, gene names and cross-references to MIM
  3. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  4. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  5. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  6. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.