KIR2DS5

Summary

KIR2DS5 (killer cell immunoglobulin like receptor, two Ig domains and short cytoplasmic tail 5, HGNC:6337) is a protein-coding gene on chromosome 19q13.4 alternate reference locus, encoding Killer cell immunoglobulin-like receptor 2DS5 (Q14953). Activating natural killer (NK) receptor that recognizes C2 epitopes of 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 3810 — RefSeq curated summary.

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6337
Approved symbol	KIR2DS5
Name	killer cell immunoglobulin like receptor, two Ig domains and short cytoplasmic tail 5
Location	19q13.4 alternate reference locus
Locus type	gene with protein product
Status	Approved
Aliases	nkat9, CD158G
OMIM	604956
Entrez	3810

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 30)

• Positive linkage disequilibrium was seen and between KIR3DS1 and KIR2DS5. (PMID:12559621)
• Carriage of activating 2ds5 was increased in patient with herpes virus RDs. (PMID:17592337)
• Donor activating KIR2DS5 may improve disease-free survival in non T-cell-depleted haploidentical hematopoietic stem cell transplantation. (PMID:18315912)
• The most frequent allele found in 132 cell lines from International Workshop samples is KIR2DS5*005, an allele characteristic of African populations. (PMID:18498296)
• The stimulatory KIR2DS5 gene was associated with improved leukemia free survival. (PMID:18555529)
• KIR2DS5 gene codes for a surface receptor triggering natural killer cell function. (PMID:18624290)
• The level of KIR2DS5 surface expression was impacted by residue 47 but that variation at several residues in the D2 domain of KIR2DS5 ultimately had a more profound effect. (PMID:18682925)
• Lack of activation KIR2DS5 may play an important role in the development of bronchiolitis obliterans but not in the control of cytomegalovirus reactivation after lung transplantation. (PMID:18765192)
• reduced allele frequency in African Americans (PMID:19410616)
• KIR2DS1 incompatibilities increased risk of relapse after allogeneic hematopoietic stem cell transplantation (PMID:19500138)
• individuals carrying three activating KIR genes 3DS1, 2DS1, and 2DS5 are more frequent in patients with Vogt-Koyanagi-Harada disease than in controls (PMID:19897003)
• The presence of KIR2DS5 gene protects human from endometriosis, ankylosing spondylitis, and acute rejection of kidney graft. (PMID:20865034)
• 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)
• KIR2DL3, KIR2DS5 and KIR2DL5B genes may be correlated with pathogenesis of nasopharyngeal carcinoma in the Chinese southern Han population. (PMID:21729574)
• increase in the allele distribution in northern province of Tehran compared with that reported for the southern Iran population (PMID:21867738)
• In summary, KIR polymorphisms may be involved in the development of Epstein-Barr virus associated hemophagocytic lymphohistiocytosis, with KIR2DS5 promoting susceptibility to this disease. (PMID:22376216)
• Data indicate that killer-cell immunoglobulin-like receptors (KIRs)activator (KIR3DS1 and KIR2DS5) and inhibitory (KIR2DL5) genes are associated with severe pandemic influenza A (H1N1) 2009 infections. (PMID:22652695)
• The activating KIR2DS5 gene was significantly increased in thyroid ancer patients compared to the controls. (PMID:22836040)
• Results suggest a protective role of KIR2DS5 in graft rejection and an association of KIR2DS4 with kidney rejection, particularly in recipients with glomerulonephritis. (PMID:23028591)
• genetic polymorphism impacts glycosylation and protein expression level (PMID:24269691)
• The presence of KIR2DS2/2DL2 with KIR2DS5 abrogated the risk of KIR2DS2/2DL2 and the protective benefit of KIR2DS5. (PMID:24571473)
• 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)
• Data show that KIR2DL5 receptor, KIR2DS1 protein, KIR2DS5 protein and KIR3DS1 receptors were all significantly associated with high viral load. (PMID:25253288)
• The presence ofKIR2DS5 reduced the risk of endometriosis if a female possessed alleles from group C2 of HLA-C. (PMID:25724317)
• study compared KIR gene repertoire of HIV-1 positive with exposed uninfected (EU)) infants to elucidate its association with transmission; results revealed presence of significantly high frequencies of activating gene KIR 2DS5 and inhibitory gene KIR 2DL3 in EU infants as compared to HIV-1 positive infants (PMID:26255774)
• KIR2DS5 gene may be protective against hypertension. (PMID:29105364)
• Study findings determined the detrimental impact of KIR2DS1, 2DS5, 3DS1, 2DL5 and CxT4 genotype on genetic predisposition to head and neck squamous cell carcinoma in Iranians. (PMID:29408295)
• Positive association of Bx genotype, KIR2L5, KIR2DS5 and full-length KIR2DS4 with the risk of meningioma. (PMID:31899050)
• Association of KIR2DL5, KIR2DS5, and KIR2DS1 allelic variation and atopic dermatitis. (PMID:36720995)
• The novel role of activating receptor KIR2DS5 in preeclampsia. (PMID:37864908)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

Killer cell immunoglobulin-like receptor 2DS5 — Q14953 (reviewed: Q14953)

Alternative names: CD158 antigen-like family member G, Natural killer-associated transcript 9

All UniProt accessions (0):

UniProt curated annotations — full annotation on UniProt →

Function. Activating natural killer (NK) receptor that recognizes C2 epitopes of HLA-C alleles. Bridging the innate and adaptive immune systems, NK cells express a number of cell surface receptors which either inhibit or stimulate their cytotoxicity. Able to activate NK cells citotoxicity and cytokine production such as IFNG. Receptor functions are attenuated even lost in some alleles, such as KIR2DS5*002 represented in this entry.

Subunit / interactions. Interacts with TYROBP.

Subcellular location. Cell membrane.

Tissue specificity. Expressed on a discrete subset of peripheral blood NK cells.

Post-translational modifications. N-glycosylated, glycosylation varies depending on the allele which alters cell surface expression levels.

Polymorphism. The following alleles are known: KIR2DS5001, KIR2DS5002, KIR2DS5003, KIR2DS5004, KIR2DS5005, KIR2DS5006, KIR2DS5007, KIR2DS5008, KIR2DS5009, KIR2DS5010 and KIR2DS5011. Allele KIR2DS5002 is represented in this entry. Allele KIR2DS5001 product is not expressed at the surface. In Europeans, KIR2DS5 is essentially monomorphic, with allele KIR2DS5002 being predominant. However, KIR2DS5 is highly polymorphic in Africans. Alleles KIR2DS5003, KIR2DS5004, KIR2DS5005, KIR2DS5006, KIR2DS5007 and KIR2DS5008 have activating potential and recocognize C2 epitopes of HLA-C alleles. Alleles KIR2DS5002, KIR2DS5009, KIR2DS5010 and KIR2DS5011 have activating potential but do not recocognize (or with very slight avidity) C2 epitopes of HLA-C alleles. Allele KIR2DS5006 protects pregnant women from pre-eclampsia. Allele KIR2DS5003 has increased glycosylation levels due to the variant Asn-144 instead of Ser-144, it also has increased cell surface expression. Alleles with variant Gly-179 instead of Arg-179 show lower levels of glycosylation.

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 (29 total): sequence variant 12, glycosylation site 4, disulfide bond 2, topological domain 2, mutagenesis site 2, domain 2, signal peptide 1, chain 1, transmembrane region 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14953-F1	79.75	0.55

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 (4): 84, 178, 223, 67

Mutagenesis-validated functional residues (2):

Position	Phenotype
68	increases expression at the cell surface.
68	reduces expression at the cell surface.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2172127	DAP12 interactions

MSigDB gene sets: 29 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_IMMUNE_RESPONSE, KEGG_ANTIGEN_PROCESSING_AND_PRESENTATION, GOMF_TRANSMEMBRANE_SIGNALING_RECEPTOR_ACTIVITY, GOBP_IMMUNE_RESPONSE_REGULATING_SIGNALING_PATHWAY, GOBP_IMMUNE_RESPONSE_INHIBITING_SIGNAL_TRANSDUCTION, GOMF_MHC_CLASS_I_RECEPTOR_ACTIVITY, REACTOME_DAP12_INTERACTIONS, GOMF_IMMUNE_RECEPTOR_ACTIVITY, GSE1460_CD4_THYMOCYTE_VS_NAIVE_CD4_TCELL_CORD_BLOOD_DN, GSE1460_CORD_VS_ADULT_BLOOD_NAIVE_CD4_TCELL_UP, KAZMIN_PBMC_P_FALCIPARUM_RTSS_AS01_AGE_UNKNOWN_CORRELATED_WITH_PROTECTION_56DY_NEGATIVE, GARCIA_PINERES_PBMC_HPV_16_L1_VLP_AGE_18_25YO_2MO_UP

GO Biological Process (2): immune response-regulating signaling pathway (GO:0002764), immune response (GO:0006955)

GO Molecular Function (1): HLA-C specific inhibitory MHC class I receptor activity (GO:0030110)

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

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signal transduction	1
regulation of immune response	1
immune system process	1
response to stimulus	1
inhibitory MHC class I receptor activity	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

46 interactions, top by confidence:

A	B	Type	Score
KIR2DS5	TYROBP	psi-mi:“MI:0915”(physical association)	0.590
KIR2DS2	RHOBTB3	psi-mi:“MI:0914”(association)	0.530
HLA-C	KIR2DS5	psi-mi:“MI:0407”(direct interaction)	0.440
KIR2DS5	HLA-C	psi-mi:“MI:0407”(direct interaction)	0.440

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), 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:604956 | 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
quercitrin	affects expression	1
CGP 52608	affects binding, increases reaction	1
Arsenic	affects expression	1
Cadmium	increases abundance, increases expression	1
Smoke	increases expression	1
Cadmium Chloride	increases abundance, increases expression	1

Clinical trials (associated diseases)

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