KIR2DS3

Summary

KIR2DS3 (killer cell immunoglobulin like receptor, two Ig domains and short cytoplasmic tail 3, HGNC:6335) is a protein-coding gene on chromosome 19q13.4 alternate reference locus, encoding Killer cell immunoglobulin-like receptor 2DS3 (Q14952). 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.

Source: NCBI Gene 3808 — RefSeq curated summary.

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6335
Approved symbol	KIR2DS3
Name	killer cell immunoglobulin like receptor, two Ig domains and short cytoplasmic tail 3
Location	19q13.4 alternate reference locus
Locus type	gene with protein product
Status	Approved
Aliases	nkat7
OMIM	604954
Entrez	3808

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 18)

• Positive linkage disequilibrium was seen between KRI2DS2 and KIR2DS3. Positive linkage disequilibrium was seen between KIR3DS1 and KIR2DS3. (PMID:12559621)
• KIR2DS3 is a protective factor for chronic graft-versus-host disease. (PMID:17462498)
• This focuses on the inheritance of KIR2DS3*001 and *002 to clarify their genetic relationship, and will investigate the diversity of haplotypes containing a KIR2DS3 gene. (PMID:18480828)
• Genomic and mRNA sequences support the KIR2DS3*002 gene being a hybrid of KIR2DS3*00103 and KIR2DS5. (PMID:18764809)
• Dramatically reduced surface expression of NK cell receptor KIR2DS3 is attributed to multiple residues throughout the molecule. (PMID:19005473)
• KIR2DS3 incompatibilities increased risk of chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation (PMID:19500138)
• KIR2DS3 is associated with protection against acute myeloid leukemia. (PMID:20371915)
• Study showed that the activating KIR2DS1 and KIR2DS3 genes associate with fatal outcome in Ebola virus infection. (PMID:20878400)
• The Natural Killer cell gene KIR2DS3 was significantly increased in patients with chronic hepatitis C virus infection. (PMID:21402922)
• KIR2DS3 and HLA-class I alleles (-Cw*14 and -Cw*17) may play a role in the pathogenesis of the Vogt-Koyanagi-Harada disease. (PMID:22219647)
• Data found that the frequencies of KIR2DS1, 2DS3 and 3DS1 were significantly higher in pulmonary tuberculosis patients than in the control group. (PMID:22653583)
• the presence of host genetic risk factors, IL28B-T and KIR2DS3 alleles, resulted in increased odds of treatment failure in these rapid virological response negative patients. (PMID:23826153)
• The genes KIR2DL5, KIR2DS3 and KIR2DS5 were present in a significantly higher proportion of individuals in the asymptomatic control group than in the malaria cases. (PMID:24929143)
• genetic polymorphism is associated with childhood acute lymphoblastic leukemia among north Indians (PMID:26472014)
• Genotypes missing these two inhibitory KIR-HLA combinations in addition to missing activating KIRs 2DS2 and 2DS3 were more common in Vogt-Koyanagi-Harada disease (OR = 1.90, P = 0.002). (PMID:27490240)
• Loss of KIR2DS3 gene is associated with breast cancer. (PMID:27631728)
• activating KIR2DS3 was associated with rapid leukocyte engraftment after hematopoietic stem cell transplantation from matched sibling (PMID:28993188)
• Clinical Impact of KIR2DS3 and KIR2DL3 Genes in Neuroblastoma Patients. (PMID:35537400)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

Killer cell immunoglobulin-like receptor 2DS3 — Q14952 (reviewed: Q14952)

Alternative names: Natural killer-associated transcript 7

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 (15 total): glycosylation site 3, disulfide bond 2, topological domain 2, domain 2, region of interest 2, signal peptide 1, chain 1, transmembrane region 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14952-F1	80.16	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): 67, 84, 178

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 27 (showing top): GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_CELLULAR_DEFENSE_RESPONSE, KEGG_ANTIGEN_PROCESSING_AND_PRESENTATION, SHEN_SMARCA2_TARGETS_DN, GOMF_TRANSMEMBRANE_SIGNALING_RECEPTOR_ACTIVITY, GOBP_IMMUNE_RESPONSE_REGULATING_SIGNALING_PATHWAY, GOBP_IMMUNE_RESPONSE_INHIBITING_SIGNAL_TRANSDUCTION, ZWANG_TRANSIENTLY_UP_BY_2ND_EGF_PULSE_ONLY, GOMF_IMMUNE_RECEPTOR_ACTIVITY, KAZMIN_PBMC_P_FALCIPARUM_RTSS_AS01_AGE_UNKNOWN_CORRELATED_WITH_PROTECTION_56DY_NEGATIVE, GSE17974_IL4_AND_ANTI_IL12_VS_UNTREATED_1H_ACT_CD4_TCELL_DN, GOBP_IMMUNE_RESPONSE_REGULATING_CELL_SURFACE_RECEPTOR_SIGNALING_PATHWAY, GSE18791_UNSTIM_VS_NEWCATSLE_VIRUS_DC_2H_UP, GOBP_REGULATION_OF_IMMUNE_SYSTEM_PROCESS, GOMF_MOLECULAR_TRANSDUCER_ACTIVITY

GO Biological Process (2): immune response-regulating signaling pathway (GO:0002764), cellular defense response (GO:0006968)

GO Molecular Function (0):

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

GO top-level categories

Rollup of top GO terms by namespace:

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

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

5 interactions, top by confidence:

A	B	Type	Score
TYROBP	KIR2DS3	psi-mi:“MI:0915”(physical association)	0.400
KIR2DS3	RTL8C	psi-mi:“MI:0914”(association)	0.350
KIR2DL1	STX6	psi-mi:“MI:0914”(association)	0.350
KIR2DL2	STX10	psi-mi:“MI:0914”(association)	0.350

BioGRID (19): TUBB8 (Affinity Capture-MS), ITPRIP (Affinity Capture-MS), KIR2DS3 (Affinity Capture-MS), LMF2 (Affinity Capture-MS), CNNM1 (Affinity Capture-MS), KIR2DS5 (Affinity Capture-MS), TUBA1C (Affinity Capture-MS), KIR2DS3 (Affinity Capture-MS), TMTC3 (Affinity Capture-MS), SH3BP4 (Affinity Capture-MS), TUBA4A (Affinity Capture-MS), EIF2AK3 (Affinity Capture-MS), D2HGDH (Affinity Capture-MS), TUBB3 (Affinity Capture-MS), POMT2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0B4J1G0, A0A0G2KBC9, A3RFZ7, B6A8R8, E2RP87, G1T7E7, G1TR84, H0VDZ8, M3XWH1, O75015, P08101, P08508, P08637, P0DTI4, P12314, P12318, P12319, P12371, P13597, P13598, P20489, P26151, P27645, P31995, P35330, P50283, P51866, P79107, P82957, Q00238, Q08481, Q09TM2, Q09TM4, Q14952, Q28942, Q3B8P2, Q3SWT0, Q5NKV1, Q5NKV2, Q60513

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), RS1001806187 (19:54750720 A>G), RS1002444288 (19:54751056 T>C), RS1003406460 (19:54745199 A>G,T), RS1005445694 (19:54751911 C>T), RS1006754208 (19:54750639 T>C), RS1006857270 (19:54749687 A>T), RS1007848963 (19:54744977 T>A,C), RS1008626417 (19:54746337 G>A,C,T), RS1008969021 (19:54747210 T>A,C), RS1009289547 (19:54751176 G>A), RS1010224004 (19:54749424 GAT>G), RS1010712251 (19:54748984 G>A,T), RS1012096980 (19:54748140 C>G,T)

Disease associations

OMIM: gene MIM:604954 | 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

3 total (human), top 3 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
CGP 52608	affects binding, increases reaction	1
Bortezomib	decreases expression	1
Smoke	increases expression	1

Clinical trials (associated diseases)

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