KIR2DL2

Summary

KIR2DL2 (killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2, HGNC:6330) is a protein-coding gene on chromosome 19q13.4 alternate reference locus, encoding Killer cell immunoglobulin-like receptor 2DL2 (P43627). Receptor on natural killer (NK) cells for HLA-Cw1, 3, 7, and 8 allotypes.

Killer cell immunoglobulin-like receptors (KIRs) are transmembrane glycoproteins expressed by natural killer cells and subsets of T cells. The KIR genes are polymorphic and highly homologous and they are found in a cluster on chromosome 19q13.4 within the 1 Mb leukocyte receptor complex (LRC). The gene content of the KIR gene cluster varies among haplotypes, although several “framework” genes are found in all haplotypes (KIR3DL3, KIR3DP1, KIR3DL4, KIR3DL2). The KIR proteins are classified by the number of extracellular immunoglobulin domains (2D or 3D) and by whether they have a long (L) or short (S) cytoplasmic domain. KIR proteins with the long cytoplasmic domain transduce inhibitory signals upon ligand binding via an immune tyrosine-based inhibitory motif (ITIM), while KIR proteins with the short cytoplasmic domain lack the ITIM motif and instead associate with the TYRO protein tyrosine kinase binding protein to transduce activating signals. The ligands for several KIR proteins are subsets of HLA class I molecules; thus, KIR proteins are thought to play an important role in regulation of the immune response.

Source: NCBI Gene 3803 — RefSeq curated summary.

At a glance

• Druggable target: yes

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6330
Approved symbol	KIR2DL2
Name	killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2
Location	19q13.4 alternate reference locus
Locus type	gene with protein product
Status	Approved
Aliases	cl-43, nkat6, CD158B1, CD158k
OMIM	604937
Entrez	3803

Gene structure

Transcript identifiers

Ensembl transcripts: 0

RefSeq mRNA: 0 — MANE Select: None

Canonical transcript exons

None — 0 exons

Expression profiles

Top tissues by expression

0 total, by Bgee expression score (0-100, higher = more expressed):

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 40)

• Individuals were subgrouped according to the major HLA-C encoded KIR-epitopes (group C1 versus C2). C2 individuals transcribe RNA from KIR2DL2 genes without specific HLA-C ligands. (PMID:12559621)
• The genetic combination of KIR2DS2+ and KIR2DL2- is associated with scleroderma. (PMID:15146426)
• KIR2DL2 is positively associated with diabetes mellitus, type 1. (PMID:15699512)
• Because few factors interfere with the expression of CD158b on natural killer cells, monitoring of this marker may be accurate and sensitive after kidney transplantation. (PMID:15848530)
• KIRs on memory T cells operate to uncouple effector functions by modifying the transcriptional profile while leaving granule exocytosis unabated. (PMID:16469873)
• Lack of KIR2DL2 is associated with poor graft function (PMID:17445184)
• In contrast to natural killer (NK) cells, the functions of killer inhibitory receptors in CD4+ T lymphocytes might derive from a selective expression of their activating or inhibiting (CD158b1) forms. (PMID:18292496)
• Allelic polymorphism at sites distal to the ligand-binding site of KIR2DL2 has diversified this receptor’s interactions with HLA-C; the interaction between the HLA-C epitope and KIR2DL2 strongly inhibits natural killer cell cytotoxicity. (PMID:18322206)
• Allele typing data support the view that KIR2DL2 and KIR2DL3 are alleles of the same gene. (PMID:18498296)
• increased frequency in recurrent spontaneous abortion group (PMID:18572300)
• The role of DNA methylation in regulating of the genes, KIR2DL2 and KIR2DL4, was characterized;these genes are normally suppressed in part by promoter methylation in non-expressing T cells. (PMID:18945643)
• a combination KIR2DL2- HLA-C1 plays a critical role in susceptibility or protection in Latvians against type 1 diabetes. (PMID:19046302)
• Natural killer (NK) cells in a humanized mouse model express multiple killer inhibitory receptors in a stochastic manner, including HLA-Cw3-specific inhibitory receptor KIR2DL2; these mice reject wild-type mouse spleen cells upon intravenous injection. (PMID:19234149)
• The inhibition of NK-cell cytotoxicity may be impaired in individuals carrying the rs2756923 G allele. These data suggest a potential role of the KIR2DL2-rs2756923 polymorphism in Type I Deabetes in Germans and Belgians. (PMID:19392800)
• a model in chronic myeloid leukemia of protection via KIR2DL2 and/or KIR2DS2 with the presence of the ligand HLA-C1 group and susceptibility via HLA-Bw4 homozygosity (i.e. absence of HLA-Bw6) was proposed. (PMID:19493232)
• DNA-demethylating treatment with 5-azacytidine resulted in re-expression of kir2DL1 gene and increased expressions of kir2DL1, kir2DL2 and kir2DL3 genes in NK-92MI cells. (PMID:19549382)
• Findings in HCV-infected and non-infected IDUs suggest an important role for KIRs (KIR2DL2 and KIR2DL3) with group HLA-C1 molecules, in the presence of activating KIR2DS4, in protection from HCV infection. (PMID:19552960)
• The KIR2DL2, KIR2DL3 genotype is predisposing to Crohn’s disease in the presence of C1 ligand. (PMID:19789864)
• Absence of KIR2DS2 and/or KIR2DL2 is associated with failure of antiviral therapy in patients with recurrent hepatitis C after liver transplantation (PMID:19877200)
• Data show that KIR activation and HLA expression density are critical determinants for the efficacy of rituximab treatment. (PMID:20056126)
• Single nucleotide polymorphism in KIR2DL2 gene is associated with posttransplantation non-Hodgkin lymphoma. (PMID:20207982)
• We report four novel KIR2DL2 alleles and two novel KIR2DL3 alleles identified from an East African population using sequence-based typing. (PMID:20875478)
• KIR2DS2/KIR2DL2 and HLA-C genotype of rheumatoid arthritis patients may provide predictive information for response to anti-TNF-alpha therapy. (PMID:21373785)
• in two unrelated viral infections, hepatitis C virus and human T lymphotropic virus type 1, possession of the KIR2DL2 gene enhanced both protective and detrimental HLA class I-restricted anti-viral immunity. (PMID:22022261)
• In a comparison of healthy controls and a tightly defined cohort of adult ITP patients, the KIR2DS2/KIR2DL2 genotype was found to be associated with ITP independently of FCGR3a-158 polymorphisms. (PMID:22024796)
• these results suggest that inhibitory KIR2DL2 and KIR2DL3, which are alleles of the same locus, play a role in the inverse effects on PM and PM/HIV co-infection (PMID:22715396)
• Amino acid variation at positions 68, 70, and 182 modulates the binding avidity of KIR2DL for histocompatibility antigen HLA-C compared to KIR2DL3. (PMID:22772445)
• Engagement of KIR2DL2 might protect virus-infected cells from NK cell-mediated lysis and selections of sequence polymorphisms that increase avidity to KIR2DL2 might provide a mechanism for HIV-1 to escape NK cell-mediated immune pressure. (PMID:22807681)
• individuals possessing KIR2DL2 and/or KIR2DS2 (and, in most cases, also KIR2DL1) gene but no HLA-C C2 ligand may respond better to treatment and survive longer than people bearing other genotypes. (PMID:22836042)
• The results are the first direct proof of the implication of KIR2DL2 receptor in the control of natural killer cell activation towards herpes virus infection in multiple sclerosis. (PMID:22871633)
• presence of KIR2DL2 is associated with rheumatoid arthritis. (PMID:22960345)
• Data indicate that increased frequency of the activating receptor KIR2DS1 and a reduced frequency of the KIR-ligand combination KIR2DS2/2DL2 absent/C1 present were significantly associated with chronic myeloid leukemia (CML). (PMID:23380384)
• the most common KIR2DL2/3 allelic products in European American and African American populations were evaluated (PMID:23686481)
• Authors showed a significant increased correlation between KIR2DL2/DS2, type 2 diabetes and HLA-C1C1 genotype in the type 2 diabetes patients infected with human herpesvirus 8. (PMID:24122895)
• combinations of KIR3DL1/HLA-Bw4, KIR2DL2/HLA-C1, and a genetic variant of the IL28B gene are predictive of the response to PEG-IFN and ribavirin therapy in Japanese patients infected with genotype 1b HCV. (PMID:24349500)
• HLA-C genotypes are important determinants of conjunctival scarring in trachoma and that KIR2DL2/KIR2DL3 heterozygosity further increases risk of conjunctival scarring in individuals carrying HLA-C2. (PMID:24651768)
• The results of this study confirmed a possible effect of KIR2DL2 on viral infection susceptibility in multiple sclerosis patients. (PMID:24735502)
• The strongest association for the development of epithelial ovarian cancer has been found between KIR2DL2 and HLA-C1 expression. (PMID:24755350)
• These data show that naturally occurring sequence variations within HLA-C03:04-restricted HIV-1 p24 Gag epitopes can have a significant impact on the binding of inhibitory KIR2DL2 receptors and primary natural killer cell function. (PMID:24785948)
• Different expression levels of KIR2DL2 may contribute to the abnormal function of natural killer (NK) and NKT lymphocytes, which lead to the risk of systemic lupus erythematosus (SLE) susceptibility. (PMID:24839813)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

Killer cell immunoglobulin-like receptor 2DL2 — P43627 (reviewed: P43627)

Alternative names: CD158 antigen-like family member B1, Natural killer-associated transcript 6, p58 natural killer cell receptor clone CL-43

All UniProt accessions (0):

UniProt curated annotations — full annotation on UniProt →

Function. Receptor on natural killer (NK) cells for HLA-Cw1, 3, 7, and 8 allotypes. Inhibits the activity of NK cells thus preventing cell lysis.

Subcellular location. Cell membrane.

Similarity. Belongs to the immunoglobulin superfamily.

RefSeq proteins (0): (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003599	Ig_sub	Domain
IPR013151	Immunoglobulin_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR050412	Ig-like_Receptors_ImmuneReg	Family

Pfam: PF00047

UniProt features (39 total): strand 21, sequence variant 3, glycosylation site 3, disulfide bond 2, topological domain 2, turn 2, domain 2, signal peptide 1, chain 1, sequence conflict 1, transmembrane region 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
9L4I	X-RAY DIFFRACTION	2.5
9LRF	X-RAY DIFFRACTION	2.5
9LRA	X-RAY DIFFRACTION	2.6
2DLI	X-RAY DIFFRACTION	2.9
8TMU	X-RAY DIFFRACTION	2.9
1EFX	X-RAY DIFFRACTION	3
2DL2	X-RAY DIFFRACTION	3
6PA1	X-RAY DIFFRACTION	3.01
9L4H	X-RAY DIFFRACTION	3.1
9LRH	X-RAY DIFFRACTION	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P43627-F1	75.16	0.50

Antibody-complex structures (SAbDab): 2 — 9LRA, 9LRF

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (2): 49–100, 149–198

Glycosylation sites (3): 84, 178, 211

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-198933	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell

MSigDB gene sets: 26 (showing top): REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_IMMUNE_RESPONSE, KEGG_GRAFT_VERSUS_HOST_DISEASE, KEGG_ANTIGEN_PROCESSING_AND_PRESENTATION, GOMF_TRANSMEMBRANE_SIGNALING_RECEPTOR_ACTIVITY, GOBP_IMMUNE_RESPONSE_REGULATING_SIGNALING_PATHWAY, GOBP_IMMUNE_RESPONSE_INHIBITING_SIGNAL_TRANSDUCTION, GOMF_IMMUNE_RECEPTOR_ACTIVITY, KAZMIN_PBMC_P_FALCIPARUM_RTSS_AS01_AGE_UNKNOWN_CORRELATED_WITH_PROTECTION_56DY_NEGATIVE, NAKAYA_PBMC_FLUARIX_FLUVIRIN_AGE_18_50YO_CORRELATED_WITH_HAI_28DY_RESPONSE_AT_3DY_POSITIVE, GOBP_IMMUNE_RESPONSE_REGULATING_CELL_SURFACE_RECEPTOR_SIGNALING_PATHWAY, GSE22886_IGM_MEMORY_BCELL_VS_BLOOD_PLASMA_CELL_UP, GSE26495_PD1HIGH_VS_PD1LOW_CD8_TCELL_DN, GSE29618_PRE_VS_DAY7_POST_LAIV_FLU_VACCINE_PDC_UP, GOBP_REGULATION_OF_IMMUNE_SYSTEM_PROCESS

GO Biological Process (1): immune response-regulating signaling pathway (GO:0002764)

GO Molecular Function (0):

GO Cellular Component (1): plasma membrane (GO:0005886)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signal transduction	1
regulation of immune response	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

19 interactions, top by confidence:

A	B	Type	Score
KIR2DL2	HLA-C	psi-mi:“MI:0407”(direct interaction)	0.610
HLA-C	KIR2DL2	psi-mi:“MI:0915”(physical association)	0.610
KIR2DL2	HLA-B	psi-mi:“MI:0407”(direct interaction)	0.440
KIR2DL2	HLA-Cw	psi-mi:“MI:0407”(direct interaction)	0.440
KIR2DL2	HLA-C	psi-mi:“MI:0407”(direct interaction)	0.440
HLA-C	KIR2DL2	psi-mi:“MI:0407”(direct interaction)	0.440
KIR2DL1	STX6	psi-mi:“MI:0914”(association)	0.350
KIR2DL2	STX10	psi-mi:“MI:0914”(association)	0.350

BioGRID (13): KIR2DL2 (Affinity Capture-MS), KIR2DL2 (Affinity Capture-MS), KIR2DL2 (Affinity Capture-MS), KIR2DL2 (Affinity Capture-MS), HLA-C (Co-crystal Structure), FAM114A2 (Affinity Capture-MS), KIR2DL2 (Affinity Capture-MS), C17orf70 (Affinity Capture-MS), KIR2DS3 (Affinity Capture-MS), MYADM (Affinity Capture-MS), VANGL1 (Affinity Capture-MS), KIR2DS2 (Affinity Capture-MS), STX10 (Affinity Capture-MS)

ESM2 similar proteins: A0A0B4J1G0, A0A0B4J1L0, A0A0G2KBC9, A1YIY0, A8MTB9, B6A8R8, C0HJX2, C0HJX3, E2RP87, H0VDZ8, P08637, P09326, P12314, P23505, P26151, P43626, P43627, P43628, P43631, P43632, P83555, P83556, Q01965, Q13291, Q14952, Q14953, Q14954, Q28942, Q2YHT5, Q61400, Q61450, Q640U3, Q68EV1, Q68SN8, Q6UX41, Q6UXE8, Q6UY09, Q6XJV4, Q6XPU4, Q7TST0

Diamond homologs: A0A0G2KBC9, A6NI73, B6A8R8, C0HJX2, C0HJX3, D3ZQX2, O75019, O75022, O75023, O76036, P0C191, P0C1X9, P24071, P43626, P43627, P43628, P43629, P43630, P43631, P43632, P59901, P83555, P83556, P97484, Q14943, Q14952, Q14953, Q14954, Q61450, Q64281, Q6GTX8, Q6ISS4, Q6PI73, Q7TQA1, Q863H2, Q8C567, Q8IYS5, Q8MJZ2, Q8MJZ7, Q8N109

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

0 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	0
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000137435 (19:54748332 C>A,T), RS1000769913 (19:54748914 A>C), RS1001149346 (19:54782731 T>G), RS1001663811 (19:54778142 T>A,C,G), RS1001764145 (19:54739741 CTG>C), RS1001806187 (19:54750720 A>G), RS1002227919 (19:54784309 C>T), RS1002444288 (19:54751056 T>C), RS1003339707 (19:54781009 A>C,G), RS1003406460 (19:54745199 A>G,T), RS1003413396 (19:54780508 T>C), RS1004045109 (19:54783521 A>C), RS1005019890 (19:54782346 A>G,T), RS1005052437 (19:54782201 A>G), RS1005235030 (19:54739229 G>C)

Disease associations

OMIM: gene MIM:604937 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3833441 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

4 total (human), top 4 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Azacitidine	affects binding, increases reaction, decreases methylation, increases expression	2
Arsenic	affects expression	1
Cadmium	decreases expression	1
Smoke	increases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.