UniProtKB - P26715 (NKG2A_HUMAN)
NKG2-A/NKG2-B type II integral membrane protein
KLRC1
Functioni
Immune inhibitory receptor involved in self-nonself discrimination. In complex with KLRD1 on cytotoxic and regulatory lymphocyte subsets, recognizes non-classical major histocompatibility (MHC) class Ib molecule HLA-E loaded with self-peptides derived from the signal sequence of classical MHC class Ia molecules. Enables cytotoxic cells to monitor the expression of MHC class I molecules in healthy cells and to tolerate self (PubMed:9486650, PubMed:18083576, PubMed:9430220).
Upon HLA-E-peptide binding, transmits intracellular signals through two immunoreceptor tyrosine-based inhibition motifs (ITIMs) by recruiting INPP5D/SHP-1 and INPPL1/SHP-2 tyrosine phosphatases to ITIMs, and ultimately opposing signals transmitted by activating receptors through dephosphorylation of proximal signaling molecules (PubMed:9485206, PubMed:12165520).
Key inhibitory receptor on natural killer (NK) cells that regulates their activation and effector functions (PubMed:9486650, PubMed:9430220, PubMed:9485206, PubMed:30860984).
Dominantly counteracts T cell receptor signaling on a subset of memory/effector CD8-positive T cells as part of an antigen-driven response to avoid autoimmunity (PubMed:12387742).
On intraepithelial CD8-positive gamma-delta regulatory T cells triggers TGFB1 secretion, which in turn limits the cytotoxic programming of intraepithelial CD8-positive alpha-beta T cells, distinguishing harmless from pathogenic antigens (PubMed:18064301).
In HLA-E-rich tumor microenvironment, acts as an immune inhibitory checkpoint and may contribute to progressive loss of effector functions of NK cells and tumor-specific T cells, a state known as cell exhaustion (PubMed:30503213, PubMed:30860984).
9 Publications(Microbial infection) Viruses like human cytomegalovirus have evolved an escape mechanism whereby virus-induced down-regulation of host MHC class I molecules is coupled to the binding of viral peptides to HLA-E, restoring HLA-E expression and inducing HLA-E-dependent NK cell immune tolerance to infected cells. Recognizes HLA-E in complex with human cytomegalovirus UL40-derived peptide (VMAPRTLIL) and inhibits NK cell cytotoxicity.
2 Publications(Microbial infection) May recognize HLA-E in complex with HIV-1 gag/Capsid protein p24-derived peptide (AISPRTLNA) on infected cells and may inhibit NK cell cytotoxicity, a mechanism that allows HIV-1 to escape immune recognition.
1 Publication(Microbial infection) Upon SARS-CoV-2 infection, may contribute to functional exhaustion of cytotoxic NK cells and CD8-positive T cells (PubMed:32203188, PubMed:32859121).
On NK cells, may recognize HLA-E in complex with SARS-CoV-2 S/Spike protein S1-derived peptide (LQPRTFLL) expressed on the surface of lung epithelial cells, inducing NK cell exhaustion and dampening antiviral immune surveillance (PubMed:32859121).
2 PublicationsGO - Molecular functioni
- carbohydrate binding Source: UniProtKB-KW
- HLA-E specific inhibitory MHC class Ib receptor activity Source: UniProtKB
- MHC class I protein complex binding Source: UniProtKB
- transmembrane signaling receptor activity Source: GO_Central
GO - Biological processi
- adaptive immune response Source: UniProtKB-KW
- CD8-positive, gamma-delta intraepithelial T cell differentiation Source: UniProtKB
- cell surface receptor signaling pathway Source: ProtInc
- innate immune response Source: UniProtKB-KW
- natural killer cell inhibitory signaling pathway Source: UniProtKB
- negative regulation of natural killer cell mediated cytotoxicity Source: UniProtKB
- negative regulation of T cell mediated cytotoxicity Source: UniProtKB
- regulation of natural killer cell activation Source: ComplexPortal
Keywordsi
Molecular function | Receptor |
Biological process | Adaptive immunity, Immunity, Innate immunity |
Ligand | Lectin |
Enzyme and pathway databases
PathwayCommonsi | P26715 |
Reactomei | R-HSA-198933, Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell |
SignaLinki | P26715 |
SIGNORi | P26715 |
Names & Taxonomyi
Protein namesi | Recommended name: NKG2-A/NKG2-B type II integral membrane proteinAlternative name(s): CD159 antigen-like family member A NK cell receptor A NKG2-A/B-activating NK receptor CD_antigen: CD159a |
Gene namesi | Name:KLRC1 Synonyms:NKG2A1 Publication |
Organismi | Homo sapiens (Human) |
Taxonomic identifieri | 9606 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Proteomesi |
|
Organism-specific databases
HGNCi | HGNC:6374, KLRC1 |
MIMi | 161555, gene |
neXtProti | NX_P26715 |
VEuPathDBi | HostDB:ENSG00000134545 |
Subcellular locationi
Plasma membrane
- Cell membrane 2 Publications; Single-pass type II membrane protein Sequence analysis
Plasma Membrane
- external side of plasma membrane Source: GO_Central
- integral component of plasma membrane Source: UniProtKB
- plasma membrane Source: ComplexPortal
Other locations
- receptor complex Source: UniProtKB
Topology
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Topological domaini | 1 – 70 | CytoplasmicSequence analysisAdd BLAST | 70 | |
Transmembranei | 71 – 93 | Helical; Signal-anchor for type II membrane proteinSequence analysisAdd BLAST | 23 | |
Topological domaini | 94 – 233 | ExtracellularSequence analysisAdd BLAST | 140 |
Keywords - Cellular componenti
Cell membrane, MembranePathology & Biotechi
Mutagenesis
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Mutagenesisi | 6 | V → A: Decreases interaction with INPP5D/SHIP-1; when associated A-38. 1 Publication | 1 | |
Mutagenesisi | 8 | Y → F: Impairs phosphorylation, interaction with INPP5D/SHIP-1 and NK cell functional inhibition; when associated F-40. 1 Publication | 1 | |
Mutagenesisi | 38 | I → A: Decreases interaction with INPP5D/SHIP-1; when associated A-6. 1 Publication | 1 | |
Mutagenesisi | 40 | Y → F: Impairs phosphorylation, interaction with INPP5D/SHIP-1 and NK cell functional inhibition; when associated F-8. 1 Publication | 1 | |
Mutagenesisi | 137 | R → A: Reduces binding to HLA-E. 1 Publication | 1 | |
Mutagenesisi | 163 | M → I: Has no impact on the affinity for HLA-E. 1 Publication | 1 | |
Mutagenesisi | 167 – 170 | SIIS → ASIL: Impairs binding to HLA-E. 1 Publication | 4 | |
Mutagenesisi | 172 | S → A: Has no impact on the affinity for HLA-E. 1 Publication | 1 | |
Mutagenesisi | 200 | D → A: Has no impact on the affinity for HLA-E. 1 Publication | 1 | |
Mutagenesisi | 202 | D → A: Has no impact on the affinity for HLA-E. 1 Publication | 1 | |
Mutagenesisi | 212 | Q → A: Reduces binding to HLA-E. 1 Publication | 1 | |
Mutagenesisi | 213 | V → A: Has no impact on the affinity for HLA-E. 1 Publication | 1 | |
Mutagenesisi | 215 | R → A: Reduces binding to HLA-E. 1 Publication | 1 | |
Mutagenesisi | 217 | K → A: Reduces binding to HLA-E. 1 Publication | 1 | |
Mutagenesisi | 220 | Q → A: Has little impact on affinity for HLA-E. 1 Publication | 1 | |
Mutagenesisi | 223 | S → A: Has no impact on affinity for HLA-E. 1 Publication | 1 |
Organism-specific databases
DisGeNETi | 3821 |
OpenTargetsi | ENSG00000134545 |
PharmGKBi | PA30163 |
Miscellaneous databases
Pharosi | P26715, Tbio |
Chemistry databases
ChEMBLi | CHEMBL4630892 |
GuidetoPHARMACOLOGYi | 2849 |
Genetic variation databases
BioMutai | KLRC1 |
DMDMi | 317373399 |
PTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
ChainiPRO_0000046659 | 1 – 233 | NKG2-A/NKG2-B type II integral membrane proteinAdd BLAST | 233 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Modified residuei | 8 | Phosphotyrosine1 Publication | 1 | |
Modified residuei | 40 | Phosphotyrosine1 Publication | 1 | |
Glycosylationi | 102 | N-linked (GlcNAc...) asparagineSequence analysis | 1 | |
Glycosylationi | 103 | N-linked (GlcNAc...) asparagineSequence analysis | 1 | |
Disulfide bondi | 116 | Interchain (with C-59 in KLRD1)1 Publication | ||
Disulfide bondi | 119 ↔ 130 | 1 Publication | ||
Disulfide bondi | 147 ↔ 229 | 1 Publication | ||
Glycosylationi | 151 | N-linked (GlcNAc...) asparagineSequence analysis | 1 | |
Glycosylationi | 180 | N-linked (GlcNAc...) asparagineSequence analysis | 1 | |
Disulfide bondi | 208 ↔ 221 | 1 Publication |
Post-translational modificationi
Keywords - PTMi
Disulfide bond, Glycoprotein, PhosphoproteinProteomic databases
jPOSTi | P26715 |
MassIVEi | P26715 |
MaxQBi | P26715 |
PaxDbi | P26715 |
PeptideAtlasi | P26715 |
PRIDEi | P26715 |
ProteomicsDBi | 54362 [P26715-1] 54363 [P26715-2] |
PTM databases
GlyGeni | P26715, 4 sites |
iPTMneti | P26715 |
PhosphoSitePlusi | P26715 |
Expressioni
Tissue specificityi
Inductioni
Gene expression databases
Bgeei | ENSG00000134545, Expressed in granulocyte and 108 other tissues |
ExpressionAtlasi | P26715, baseline and differential |
Genevisiblei | P26715, HS |
Organism-specific databases
HPAi | ENSG00000134545, Tissue enhanced (lymphoid) |
Interactioni
Subunit structurei
Heterodimer with KLRD1; disulfide-linked (PubMed:18083576, PubMed:18332182, PubMed:18448674). KLRD1-KLRC1 heterodimer interacts with peptide-bound HLA-E-B2M heterotrimeric complex (PubMed:18083576). Competes with KLRC2 for its interaction with HLA-E (PubMed:18083576).
Interacts (via ITIM) with INPP5D/SHIP-1 and INPPL1/SHIP-2 (via SH2 domain).
5 PublicationsBinary interactionsi
P26715
Protein-protein interaction databases
BioGRIDi | 110020, 162 interactors |
ComplexPortali | CPX-2502, CD94-NKG2A natural killer receptor complex |
ELMi | P26715 |
IntActi | P26715, 49 interactors |
STRINGi | 9606.ENSP00000438038 |
Miscellaneous databases
RNActi | P26715, protein |
Structurei
Secondary structure
3D structure databases
AlphaFoldDBi | P26715 |
SMRi | P26715 |
ModBasei | Search... |
PDBe-KBi | Search... |
Miscellaneous databases
EvolutionaryTracei | P26715 |
Family & Domainsi
Domains and Repeats
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Domaini | 118 – 231 | C-type lectinPROSITE-ProRule annotationAdd BLAST | 114 |
Region
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Regioni | 1 – 29 | DisorderedSequence analysisAdd BLAST | 29 |
Motif
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Motifi | 6 – 11 | Immunoreceptor tyrosine-based inhibition motif (ITIM)1 Publication | 6 | |
Motifi | 38 – 43 | Immunoreceptor tyrosine-based inhibition motif (ITIM)1 Publication | 6 |
Compositional bias
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Compositional biasi | 1 – 16 | Polar residuesSequence analysisAdd BLAST | 16 |
Domaini
Keywords - Domaini
Signal-anchor, Transmembrane, Transmembrane helixPhylogenomic databases
eggNOGi | ENOG502S6IE, Eukaryota |
GeneTreei | ENSGT00940000164619 |
HOGENOMi | CLU_049894_9_2_1 |
InParanoidi | P26715 |
OMAi | KEWLIYS |
OrthoDBi | 1161111at2759 |
PhylomeDBi | P26715 |
TreeFami | TF336674 |
Family and domain databases
CDDi | cd03593, CLECT_NK_receptors_like, 1 hit |
Gene3Di | 3.10.100.10, 1 hit |
InterProi | View protein in InterPro IPR001304, C-type_lectin-like IPR016186, C-type_lectin-like/link_sf IPR016187, CTDL_fold IPR033992, NKR-like_CTLD |
Pfami | View protein in Pfam PF00059, Lectin_C, 1 hit |
SMARTi | View protein in SMART SM00034, CLECT, 1 hit |
SUPFAMi | SSF56436, SSF56436, 1 hit |
PROSITEi | View protein in PROSITE PS50041, C_TYPE_LECTIN_2, 1 hit |
s (2+)i Sequence
Sequence statusi: Complete.
This entry describes 2 produced by isoformsialternative splicing. AlignAdd to basketThis entry has 2 described isoforms and 2 potential isoforms that are computationally mapped.Show allAlign All
This isoform has been chosen as the sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry. canonicali
10 20 30 40 50
MDNQGVIYSD LNLPPNPKRQ QRKPKGNKNS ILATEQEITY AELNLQKASQ
60 70 80 90 100
DFQGNDKTYH CKDLPSAPEK LIVGILGIIC LILMASVVTI VVIPSTLIQR
110 120 130 140 150
HNNSSLNTRT QKARHCGHCP EEWITYSNSC YYIGKERRTW EESLLACTSK
160 170 180 190 200
NSSLLSIDNE EEMKFLSIIS PSSWIGVFRN SSHHPWVTMN GLAFKHEIKD
210 220 230
SDNAELNCAV LQVNRLKSAQ CGSSIIYHCK HKL
The sequence of this isoform differs from the canonical sequence as follows:
96-113: Missing.
Computationally mapped potential isoform sequencesi
There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basketF5GYZ0 | F5GYZ0_HUMAN | NKG2-A/NKG2-B type II integral memb... | KLRC1 | 228 | Annotation score: | ||
H0YGB7 | H0YGB7_HUMAN | NKG2-A/NKG2-B type II integral memb... | KLRC1 | 77 | Annotation score: |
Natural variant
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Natural variantiVAR_050120 | 29 | N → S5 PublicationsCorresponds to variant dbSNP:rs2253849Ensembl. | 1 |
Alternative sequence
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Alternative sequenceiVSP_003062 | 96 – 113 | Missing in isoform NKG2-B. 2 PublicationsAdd BLAST | 18 |
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | X54867 mRNA Translation: CAA38649.1 X54868 mRNA Translation: CAA38650.1 U54786 , U54783, U54784, U54785 Genomic DNA Translation: AAB17133.1 AF023840 Genomic DNA Translation: AAC17488.1 AF461812 mRNA Translation: AAL65234.1 AC068775 Genomic DNA No translation available. BC012550 mRNA Translation: AAH12550.1 BC053840 mRNA Translation: AAH53840.1 |
CCDSi | CCDS8625.1 [P26715-1] CCDS8626.1 [P26715-2] |
PIRi | PT0372 |
RefSeqi | NP_002250.1, NM_002259.4 [P26715-1] NP_015567.1, NM_007328.3 [P26715-2] NP_998822.1, NM_213657.2 NP_998823.1, NM_213658.2 |
Genome annotation databases
Ensembli | ENST00000347831.9; ENSP00000256965.7; ENSG00000134545.14 [P26715-2] ENST00000359151.8; ENSP00000352064.3; ENSG00000134545.14 ENST00000408006.7; ENSP00000385304.3; ENSG00000134545.14 [P26715-2] ENST00000544822.2; ENSP00000438038.1; ENSG00000134545.14 |
GeneIDi | 3821 |
KEGGi | hsa:3821 |
MANE-Selecti | ENST00000359151.8; ENSP00000352064.3; NM_002259.5; NP_002250.2 |
UCSCi | uc001qyl.5, human [P26715-1] |
Keywords - Coding sequence diversityi
Alternative splicingSimilar proteinsi
Cross-referencesi
Web resourcesi
Functional Glycomics Gateway - Glycan Binding NKG-2A |
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | X54867 mRNA Translation: CAA38649.1 X54868 mRNA Translation: CAA38650.1 U54786 , U54783, U54784, U54785 Genomic DNA Translation: AAB17133.1 AF023840 Genomic DNA Translation: AAC17488.1 AF461812 mRNA Translation: AAL65234.1 AC068775 Genomic DNA No translation available. BC012550 mRNA Translation: AAH12550.1 BC053840 mRNA Translation: AAH53840.1 |
CCDSi | CCDS8625.1 [P26715-1] CCDS8626.1 [P26715-2] |
PIRi | PT0372 |
RefSeqi | NP_002250.1, NM_002259.4 [P26715-1] NP_015567.1, NM_007328.3 [P26715-2] NP_998822.1, NM_213657.2 NP_998823.1, NM_213658.2 |
3D structure databases
Select the link destinations: PDBei RCSB PDBi PDBji Links Updated | PDB entry | Method | Resolution (Å) | Chain | Positions | PDBsum |
2RMX | NMR | - | B | 1-15 | [»] | |
2YU7 | NMR | - | B | 33-47 | [»] | |
3BDW | X-ray | 2.50 | B/D | 113-232 | [»] | |
3CDG | X-ray | 3.40 | F/K | 113-232 | [»] | |
3CII | X-ray | 4.41 | H/J | 113-232 | [»] | |
AlphaFoldDBi | P26715 | |||||
SMRi | P26715 | |||||
ModBasei | Search... | |||||
PDBe-KBi | Search... |
Protein-protein interaction databases
BioGRIDi | 110020, 162 interactors |
ComplexPortali | CPX-2502, CD94-NKG2A natural killer receptor complex |
ELMi | P26715 |
IntActi | P26715, 49 interactors |
STRINGi | 9606.ENSP00000438038 |
Chemistry databases
ChEMBLi | CHEMBL4630892 |
GuidetoPHARMACOLOGYi | 2849 |
PTM databases
GlyGeni | P26715, 4 sites |
iPTMneti | P26715 |
PhosphoSitePlusi | P26715 |
Genetic variation databases
BioMutai | KLRC1 |
DMDMi | 317373399 |
Proteomic databases
jPOSTi | P26715 |
MassIVEi | P26715 |
MaxQBi | P26715 |
PaxDbi | P26715 |
PeptideAtlasi | P26715 |
PRIDEi | P26715 |
ProteomicsDBi | 54362 [P26715-1] 54363 [P26715-2] |
Protocols and materials databases
ABCDi | P26715, 1 sequenced antibody |
Antibodypediai | 23336, 622 antibodies from 35 providers |
DNASUi | 3821 |
Genome annotation databases
Ensembli | ENST00000347831.9; ENSP00000256965.7; ENSG00000134545.14 [P26715-2] ENST00000359151.8; ENSP00000352064.3; ENSG00000134545.14 ENST00000408006.7; ENSP00000385304.3; ENSG00000134545.14 [P26715-2] ENST00000544822.2; ENSP00000438038.1; ENSG00000134545.14 |
GeneIDi | 3821 |
KEGGi | hsa:3821 |
MANE-Selecti | ENST00000359151.8; ENSP00000352064.3; NM_002259.5; NP_002250.2 |
UCSCi | uc001qyl.5, human [P26715-1] |
Organism-specific databases
CTDi | 3821 |
DisGeNETi | 3821 |
GeneCardsi | KLRC1 |
HGNCi | HGNC:6374, KLRC1 |
HPAi | ENSG00000134545, Tissue enhanced (lymphoid) |
MIMi | 161555, gene |
neXtProti | NX_P26715 |
OpenTargetsi | ENSG00000134545 |
PharmGKBi | PA30163 |
VEuPathDBi | HostDB:ENSG00000134545 |
GenAtlasi | Search... |
Phylogenomic databases
eggNOGi | ENOG502S6IE, Eukaryota |
GeneTreei | ENSGT00940000164619 |
HOGENOMi | CLU_049894_9_2_1 |
InParanoidi | P26715 |
OMAi | KEWLIYS |
OrthoDBi | 1161111at2759 |
PhylomeDBi | P26715 |
TreeFami | TF336674 |
Enzyme and pathway databases
PathwayCommonsi | P26715 |
Reactomei | R-HSA-198933, Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell |
SignaLinki | P26715 |
SIGNORi | P26715 |
Miscellaneous databases
BioGRID-ORCSi | 3821, 6 hits in 1037 CRISPR screens |
EvolutionaryTracei | P26715 |
GenomeRNAii | 3821 |
Pharosi | P26715, Tbio |
PROi | PR:P26715 |
RNActi | P26715, protein |
SOURCEi | Search... |
Gene expression databases
Bgeei | ENSG00000134545, Expressed in granulocyte and 108 other tissues |
ExpressionAtlasi | P26715, baseline and differential |
Genevisiblei | P26715, HS |
Family and domain databases
CDDi | cd03593, CLECT_NK_receptors_like, 1 hit |
Gene3Di | 3.10.100.10, 1 hit |
InterProi | View protein in InterPro IPR001304, C-type_lectin-like IPR016186, C-type_lectin-like/link_sf IPR016187, CTDL_fold IPR033992, NKR-like_CTLD |
Pfami | View protein in Pfam PF00059, Lectin_C, 1 hit |
SMARTi | View protein in SMART SM00034, CLECT, 1 hit |
SUPFAMi | SSF56436, SSF56436, 1 hit |
PROSITEi | View protein in PROSITE PS50041, C_TYPE_LECTIN_2, 1 hit |
MobiDBi | Search... |
Entry informationi
Entry namei | NKG2A_HUMAN | |
Accessioni | P26715Primary (citable) accession number: P26715 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | August 1, 1992 |
Last sequence update: | January 11, 2011 | |
Last modified: | May 25, 2022 | |
This is version 191 of the entry and version 2 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Chordata Protein Annotation Program | |
Disclaimer | Any 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
3D-structure, Reference proteomeDocuments
- Human cell differentiation molecules
CD nomenclature of surface proteins of human leucocytes and list of entries - Human chromosome 12
Human chromosome 12: entries, gene names and cross-references to MIM - Human entries with genetic variants
List of human entries with genetic variants - Human variants curated from literature reports
Index of human variants curated from literature reports - MIM cross-references
Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot - PDB cross-references
Index of Protein Data Bank (PDB) cross-references