KIR2DS2

Summary

KIR2DS2 (killer cell immunoglobulin like receptor, two Ig domains and short cytoplasmic tail 2, HGNC:6334) is a protein-coding gene on chromosome 19q13.4 alternate reference locus, encoding Killer cell immunoglobulin-like receptor 2DS2 (P43631). Receptor on natural killer (NK) cells for HLA-C alleles.

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. This gene represents a haplotype-specific family member that encodes a protein with a short cytoplasmic tail. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 100132285 — RefSeq curated summary.

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6334
Approved symbol	KIR2DS2
Name	killer cell immunoglobulin like receptor, two Ig domains and short cytoplasmic tail 2
Location	19q13.4 alternate reference locus
Locus type	gene with protein product
Status	Approved
Aliases	cl-49, nkat5, 183ActI, CD158J
OMIM	604953
Entrez	100132285

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)

• Positive linkage disequilibrium was seen between KRI2DS2 and KIR2DS3. (PMID:12559621)
• CD158j in T cells functions as a costimulatory molecule through the JNK pathway independent of KARAP/DAP12 and DAP10. (PMID:12591902)
• Crystal structure of the human natural killer cell activating receptor KIR2DS2 (CD158j). (PMID:12668644)
• An increase in activating KIR2DS2-HLA ligand pairs combined with a lack of inhibitory KIR-HLA ligand pairs is associated with an additional risk to develop type 1 diabetes in individuals with diabetes high-risk HLA alleles. (PMID:14514651)
• The genetic combination of KIR2DS2+ and KIR2DL2- is associated with scleroderma. (PMID:15146426)
• KIR2DS2 associates with alternative adapter molecules (e.g., KARAP/DAP12), leading to differential signaling mechanisms and cellular activation. (PMID:15356118)
• KIR2DS2 is positively associated with diabetes mellitus, type 1. (PMID:15699512)
• The presence of KIR2DS2 gene in the donor is associated with a high risk of mortality following unrelated donor-hematopoietic cell transplantation. (PMID:16504727)
• A study evaluating how transmembrane sequences flanking the polar interaction site contribute to assembly for three receptors that associate with different signaling modules is presented. (PMID:16623599)
• Significantly increased KIR2DS2 is associated with systemic lupus erythematosus and scleroderma (PMID:17445179)
• Lack of KIR2DS2 is associated with poor graft function (PMID:17445184)
• Data show that there was no correlation between CD158b expression and disease activity in rheumatoid arthritis. (PMID:17497034)
• 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 (CD158j) or inhibiting forms. (PMID:18292496)
• A profound effect of KIR2DS2/S3/S4 in the absence of strong inhibition may enhance the activation of natural killer cells and T-cell subsets against intraocular self-antigens, thereby contributing to pathogenesis of birdshot chorioretinopathy. (PMID:18340360)
• KIR gene frequencies in Poles are close to these in other Caucasoids but different from those in Asian and African populations, and particularly distant from those in Australian Aborigines (PMID:18976447)
• reduced allele frequency in African Americans (PMID:19410616)
• 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)
• Data show that sHLA-Cw4 or sHLA-Cw3 alleles induced secretion of TGF-beta1 by ligation of stimulatory KIR2DS1 or KIR2DS2 isoforms. (PMID:19830740)
• Absence of KIR2DS2 and/or KIR2DL2 is associated with failure of antiviral therapy in patients with recurrent hepatitis C after liver transplantation (PMID:19877200)
• Single nucleotide polymorphism in KIR2DS2 gene is associated with posttransplantation non-Hodgkin lymphoma. (PMID:20207982)
• an evolutionary trend toward reducing the avidity of the activating C1- and C2-specific receptors is exempllified by KIR2DS2, an activating C1-specific receptor that has lost all detectable avidity for HLA class I. (PMID:20802150)
• indicated nonspecific stimulation of natural killers, probably mediated by an increase in serum concentration of heat shock protein with a molecular weight of 70 kDa (PMID:21165439)
• predisposition to systemic lupus erythematosus was associated with GTGT deletion at the SLC11A1 3’UTR, presence of KIR2DS2 +/KIR2DS5 +/KIR3DS1 + profile, increased number of stimulatory KIR genes and European and Amerindian ancestries (PMID:21233146)
• KIR2DS2/KIR2DL2 and HLA-C genotype of rheumatoid arthritis patients may provide predictive information for response to anti-TNF-alpha therapy. (PMID:21373785)
• KIR2DS2*005 encodes a molecule expressed on the surface of natural killer- and T-lymphocytes. (PMID:21593779)
• The CMV seropositivity of donors was not associated with activating KIR expression, and donor null expression in those with the KIR2DS2 or KIR2DS4 genotype was not predictive for CMV reactivation in the recipient. (PMID:21596150)
• 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)
• This study showed a significantly lower frequency of KIR2DS2 among chronic HCV carriers compared with controls in a Korean population (PMID:22065905)
• The frequency of the combination of HLA-C1 allele group with KIR2DS2 was significantly higher in severe dry eye disease patients. (PMID:22509813)
• 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)
• in response to HCT therapy, the activating receptors are also enhanced by a process that increases the number of unmethylated sites present on KIR2DS2/4 promoters. (PMID:22939905)
• presence of KIR2DS2 is associated with rheumatoid arthritis. (PMID:22960345)
• Our data revealed a unique contribution of activating KIRs (KIR2DS4, KIR2DS2, or KIR3DS1), in addition to NKG2C, in the expansion of human natural killer cells. (PMID:23325834)
• 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)
• Analysis of this large cohort from Uganda in the context of other African populations reveals variations in KIR and HLA-C1 and C2 that are consistent with migrations within Africa and potential selection pressures on these genes. (PMID:23974321)
• 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)
• There is an association of the KIR2DS gene, especially KIR2DS2, with psoriatic arthritis. (PMID:24185760)
• Activating killer cell immunoglobulin-like receptor 2DS2 binds to HLA-A*11. (PMID:24550293)
• NK cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong animal survival. (PMID:25381437)
• CD4(+) CD28(-) cells exhibited increased KIR2DS2, reduced KIR2DL3 and increased DAP12 expression in HD-ESRD compared with NDD-CKD patients. (PMID:25484131)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

Killer cell immunoglobulin-like receptor 2DS2 — P43631 (reviewed: P43631)

Alternative names: CD158 antigen-like family member J, NK receptor 183 ActI, Natural killer-associated transcript 5, p58 natural killer cell receptor clone CL-49

All UniProt accessions (0):

UniProt curated annotations — full annotation on UniProt →

Function. Receptor on natural killer (NK) cells for HLA-C alleles. Does not inhibit the activity of NK cells.

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 19, sequence variant 4, glycosylation site 3, disulfide bond 2, topological domain 2, domain 2, region of interest 2, signal peptide 1, chain 1, sequence conflict 1, helix 1, transmembrane region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
1M4K	X-RAY DIFFRACTION	2.3
4N8V	X-RAY DIFFRACTION	2.5
7DUU	X-RAY DIFFRACTION	2.51

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P43631-F1	80.86	0.59

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): 178, 211, 84

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-198933	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell
R-HSA-2172127	DAP12 interactions

MSigDB gene sets: 48 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GNF2_IL2RB, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_REGULATION_OF_DEFENSE_RESPONSE, GOBP_ACTIVATION_OF_INNATE_IMMUNE_RESPONSE, GNF2_PTPN4, GOMF_TRANSMEMBRANE_SIGNALING_RECEPTOR_ACTIVITY, GOBP_ACTIVATION_OF_IMMUNE_RESPONSE

GO Biological Process (3): stimulatory killer cell immunoglobulin-like receptor signaling pathway (GO:0002222), immune response-regulating signaling pathway (GO:0002764), immune response (GO:0006955)

GO Molecular Function (1): transmembrane signaling receptor activity (GO:0004888)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Adaptive Immune System	1
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
innate immune response activating cell surface receptor signaling pathway	1
signal transduction	1
regulation of immune response	1
immune system process	1
response to stimulus	1
signaling receptor activity	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

5 interactions, top by confidence:

A	B	Type	Score
KIR2DS2	RHOBTB3	psi-mi:“MI:0914”(association)	0.530
KIR2DS2	LTN1	psi-mi:“MI:0914”(association)	0.350
KIR2DS3	RTL8C	psi-mi:“MI:0914”(association)	0.350
KIR2DL2	STX10	psi-mi:“MI:0914”(association)	0.350

BioGRID (171): ANXA1 (Affinity Capture-MS), INTS12 (Affinity Capture-MS), EXOC1 (Affinity Capture-MS), KIR3DP1 (Affinity Capture-MS), KIR2DS5 (Affinity Capture-MS), KIR2DS1 (Affinity Capture-MS), KIR3DL1 (Affinity Capture-MS), FASTKD1 (Affinity Capture-MS), CST4 (Affinity Capture-MS), CST1 (Affinity Capture-MS), CST2 (Affinity Capture-MS), LTN1 (Affinity Capture-MS), CHD1L (Affinity Capture-MS), RHOBTB3 (Affinity Capture-MS), ZG16B (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): RS1001764145 (19:54739741 CTG>C), RS1005260637 (19:54738196 T>C), RS1005391828 (19:54738951 T>A,C,G), RS1006240523 (19:54734443 A>G), RS1008032877 (19:54733838 G>C), RS1008063788 (19:54733522 C>CA), RS1008609098 (19:54732126 G>A), RS1009706301 (19:54737840 T>G), RS1009735726 (19:54737071 A>C,G), RS1010891055 (19:54754849 G>A,C), RS1012108078 (19:54744521 A>C), RS1013154862 (19:54744114 T>C), RS1013322229 (19:54733268 C>T), RS1014963125 (19:54734632 T>G), RS1015035167 (19:54733968 A>G)

Disease associations

OMIM: gene MIM:604953 | 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: no

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

CTD chemical–gene interactions

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
CGP 52608	affects binding, increases reaction	1
Cadmium	decreases expression	1
Methotrexate	decreases expression	1
Smoke	increases expression	1
Sodium Selenite	increases expression	1
Simvastatin	decreases expression	1

Clinical trials (associated diseases)

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