KIR2DS1

Summary

KIR2DS1 (killer cell immunoglobulin like receptor, two Ig domains and short cytoplasmic tail 1, HGNC:6333) is a protein-coding gene on chromosome 19q13.4 alternate reference locus, encoding Killer cell immunoglobulin-like receptor 2DS1 (Q14954). Receptor on natural killer (NK) cells for some HLA-C alleles such as w6.

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 3806 — RefSeq curated summary.

At a glance

• MANE Select transcript: NM_014218

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6333
Approved symbol	KIR2DS1
Name	killer cell immunoglobulin like receptor, two Ig domains and short cytoplasmic tail 1
Location	19q13.4 alternate reference locus
Locus type	gene with protein product
Status	Approved
Aliases	EB6ActI, EB6ActII, CD158H
Ensembl gene	ENSG00000276387
OMIM	604952
Entrez	3806

Gene structure

Transcript identifiers

Ensembl transcripts: 0

RefSeq mRNA: 1 — MANE Select: NM_014218 NM_014218

Canonical transcript exons

ENST00000336077 — 8 exons

Exon	Start	End
ENSE00001900463	54783637	54784322
ENSE00001920028	54769793	54769884
ENSE00002516631	54778612	54778662
ENSE00002519960	54773333	54773632
ENSE00002534224	54775165	54775458
ENSE00003472195	54782922	54783023
ENSE00003553013	54783486	54783538
ENSE00003649082	54770849	54770884

Expression profiles

Top tissues by expression

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

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-CURD-84	yes	86.80

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 40)

• KIR2DS1 genes are overrepresented in combination with KIR2DS3, KIR3DS1 and KIR2DS5. (PMID:12559621)
• The frequencies of KIR2DS1 and KIR2DL5 were significantly increased in psoriasis vulgaris cases compared with controls (PMID:15140215)
• Results indicate a role of KIR2DS1 on recognition of HLA-Cw6 in susceptibility to psoriasis. (PMID:15310528)
• An increase in the frequency of the activating KIR2DS1 gene was detected in the psoriatic arthritis (PsA) patients, compared with psoriasis patients negative for PsA and an unaffected American Caucasian control group. (PMID:16112031)
• KIR2DS1 and KIR2DL1 share sensitivity to peptide sequence alterations. These results fit a model in which activating and inhibitory receptors recognize the same sets of self-MHC class I molecules, differing only in their binding affinities. (PMID:16141329)
• The presence of KIR2DS1 in the donor (n = 16/25) was not demonstrated to influence outcome following donor-hematopoietic cell transplantation. (PMID:16504727)
• Significantly increased KIR2DS1 is associated with systemic lupus erythematosus and scleroderma (PMID:17445179)
• These results suggest that activating KIR2DS1 gene may not confer susceptibility to PV, and an association of KIR2DS1 gene with the HLA-Cw*0602+ was observed in these patients. (PMID:18643961)
• The role of this investigation has been to create a base of genetic information in relation to both KIR2DL1 and KIR2DS1 allele diversity. (PMID:18643963)
• KIR2DS1 incompatibilities increased risk of chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation (PMID:19500138)
• Data show that sHLA-Cw4 or sHLA-Cw3 alleles induced secretion of TGF-beta1 by ligation of stimulatory KIR2DS1 or KIR2DS2 isoforms. (PMID:19830740)
• KIR3DS1 and KIR2DS1 may be necessary to trigger an effective early immune response against HPV-infected targets to establish resistance to recurrent respiratory papillomatosis (PMID:19861144)
• 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)
• KIR2DS1 has been associated with autoimmunity and hematopoietic stem cell transplantation, these results pave the way to dissect the function of KIR2DS1 in these clinical conditions. (PMID:20093094)
• This study suggested that the presence of functional compounds of activating KIR receptors together with their HLA ligands, allowing the immunomodulatory function of NK cells, may have a protective role against the disease. (PMID:20826009)
• Study showed that the activating KIR2DS1 and KIR2DS3 genes associate with fatal outcome in Ebola virus infection. (PMID:20878400)
• In alloreactive natural killer-cell responses, KIR2DS1 expression represents a remarkable advantage as it allows efficient killing of C2/C2 or C1/C2 myelomonocitic dendritic cells (DCs) and T-cell blasts. (PMID:21355085)
• High KIR2DS1 activation is associated with breast cancer. (PMID:21479698)
• KIR2DS1 expression may also significantly amplify the size of the alloreactive NK cell subset by switching a subset of “not alloreactive” NK cells into potent alloreactive cells. (PMID:21791599)
• In this study, KIR2DS1+HLA-C2 and KIR3DL1+HLA-B Bw4 Ile80 combinations were associated with the vulnerability to ankylosing spondylitis. (PMID:21797986)
• in this cohort, KIR2DS1(+) patients had significantly lower 2-year probabilities of achieving CCyR and OS than KIR2DS1(-) patients. The impact of KIR2DS1 on CCyR was greatest when the ligand for the corresponding inhibitory receptor, KIR2DL1, was absent (PMID:21844874)
• Data found that the frequencies of KIR2DS1, 2DS3 and 3DS1 were significantly higher in pulmonary tuberculosis patients than in the control group. (PMID:22653583)
• Activating KIR genes from donors were associated with distinct outcomes of allogeneic HSCT for AML. Donor KIR2DS1 appeared to provide protection against relapse in an HLA-C-dependent manner, and donor KIR3DS1 was associated with reduced mortality. (PMID:22931314)
• 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)
• many NK cells with anti-HLA-C2 reactivity are present in HLA-C1 homozygous and heterozygous donors with KIR2DS1. (PMID:23554313)
• Frequencies of the great majority of KIR genes did not differ between patients and controls, except for KIR2DS1, whose frequency was significantly lower in patients than in controls (PMID:23831511)
• Activation of KIR2DS1 positive decidual natural killer cells by HLA-C2 stimulated production of soluble products including GM-CSF. (PMID:24091323)
• A negative association was found between the activating KIR2DS1 gene and multiple sclerosis. (PMID:24529855)
• Effect of KIR2DS1 was most significant in pregnancies where its ligand, HLA-C2, was paternally but not maternally inherited by a fetus (p = 0.005, odds ratio = 2.65). (PMID:24778445)
• Different expression levels of KIR2DL1 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)
• frequency of the maternal KIR2DS1 gene lower in the preeclampsia group than control group (PMID:24911933)
• Data show that KIR2DL5 receptor, KIR2DS1 protein, KIR2DS5 protein and KIR3DS1 receptors were all significantly associated with high viral load. (PMID:25253288)
• Moreover, the frequency of activating genotypes in the AS patient group was significantly higher than in the healthy control group (P < 0.05). KIR2DS1 and KIR3DS1 (PMID:25491925)
• the frequencies of HLA-Cw07 were statistically significantly higher in the patient group than those in the control group (P = 0.009). KIR2DS1(+) HLA(-) Cw(Lys) was more common in subjects with SLE (PMID:25581336)
• Absence of HLA-C2 for donor KIR2DL1 was associated with higher grade II to IV (HR, 1.4; P = .002) and III to IV acute GVHD (HR, 1.5; P = .01) compared with HLA-C2(+) patients. (PMID:25960307)
• KIR2DS1-C2C2 is less frequent in type 1 diabetes in Saudi children (PMID:26542066)
• Recurrent Pregnancy Loss in Women with Killer Cell Immunoglobulin-Like Receptor KIR2DS1 is Associated with an Increased HLA-C2 Allelic Frequency (PMID:26589762)
• functional interactions between KIR and HLA modify risks of BCC and SCC and that KIR encoded by the B genes provides selective pressure for altered p53 in BCC tumors. (PMID:26744525)
• The activating KIR gene KIR2DS1 has an important predictive potential for early onset of type 1 autoimmune hepatitis. (PMID:26744892)
• KIR2DS1 gene polymorphism is associated with HIV-1 infection. (PMID:26888639)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

Killer cell immunoglobulin-like receptor 2DS1 — Q14954 (reviewed: Q14954)

Alternative names: CD158 antigen-like family member H, MHC class I NK cell receptor Eb6 ActI

All UniProt accessions (2): A0A0G2JNJ6, B1N8M6

UniProt curated annotations — full annotation on UniProt →

Function. Receptor on natural killer (NK) cells for some HLA-C alleles such as w6. Does not inhibit the activity of NK cells.

Subunit / interactions. Interacts with the adapter protein TYROBP/DAP12; the interaction enhances KIR2DS1 stability at the cell surface.

Subcellular location. Cell membrane.

Tissue specificity. Expressed by NK cells.

Similarity. Belongs to the immunoglobulin superfamily.

RefSeq proteins (1): NP_055033* (*=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 (18 total): glycosylation site 4, disulfide bond 2, sequence variant 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-Q14954-F1	81.28	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 (4): 67, 84, 144, 178

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: 22 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_ADAPTIVE_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, ATF2_UP.V1_UP, REACTOME_DAP12_INTERACTIONS, DCA_UP.V1_UP, PDGF_UP.V1_DN, GOMF_IMMUNE_RECEPTOR_ACTIVITY, GSE1432_CTRL_VS_IFNG_1H_MICROGLIA_UP, KAZMIN_PBMC_P_FALCIPARUM_RTSS_AS01_AGE_UNKNOWN_CORRELATED_WITH_PROTECTION_56DY_NEGATIVE, GOBP_IMMUNE_RESPONSE_REGULATING_CELL_SURFACE_RECEPTOR_SIGNALING_PATHWAY

GO Biological Process (2): 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
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

14 interactions, top by confidence:

A	B	Type	Score
KIR2DS1	HLA-C	psi-mi:“MI:0407”(direct interaction)	0.610
HLA-C	KIR2DS1	psi-mi:“MI:0407”(direct interaction)	0.610
KIR2DS1	HLA-C	psi-mi:“MI:0915”(physical association)	0.610
KIR2DS2	RHOBTB3	psi-mi:“MI:0914”(association)	0.530
KIR2DS1	HLA-C	psi-mi:“MI:0407”(direct interaction)	0.440
B2M		psi-mi:“MI:0915”(physical association)	0.400
KIR2DS2	LTN1	psi-mi:“MI:0914”(association)	0.350
KIR2DS1	cya	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (4): KIR2DS1 (Affinity Capture-MS), KIR2DS1 (Affinity Capture-MS), KIR2DS1 (Affinity Capture-MS), KIR2DS1 (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, C0HJX2, C0HJX3, D3ZQX2, O75019, O75022, O75023, O76036, P0C191, P24071, P43626, P43629, P43630, P59901, P83556, P97484, Q14943, Q14954, Q61450, Q64281, Q6GTX8, Q6ISS4, Q6PI73, Q7TQA1, Q863H2, Q8C567, Q8IYS5, Q8MJZ2, Q8MJZ7, Q8N109, Q8N149, Q8N423, Q8N6C8, Q8N743, Q8NHJ6, Q8NHK3, Q8NHL6, Q95JB9, Q9HCN6

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

2263 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:54773605:A:C	S115R	0.943
19:54773607:T:A	S115R	0.943
19:54773607:T:G	S115R	0.943
19:54775347:T:C	F185L	0.919
19:54775349:T:A	F185L	0.919
19:54775349:T:G	F185L	0.919
19:54773434:T:C	F58L	0.915
19:54773436:C:A	F58L	0.915
19:54773436:C:G	F58L	0.915
19:54775431:A:C	S213R	0.906
19:54775433:T:A	S213R	0.906
19:54775433:T:G	S213R	0.906
19:54775239:T:A	C149S	0.893
19:54775240:G:C	C149S	0.893
19:54769869:A:C	S7R	0.885
19:54769871:C:A	S7R	0.885
19:54769871:C:G	S7R	0.885
19:54773560:T:A	C100S	0.884
19:54773561:G:C	C100S	0.884
19:54775389:T:C	F199L	0.880
19:54775391:C:A	F199L	0.880
19:54775391:C:G	F199L	0.880
19:54773515:T:C	F85L	0.878
19:54773517:C:A	F85L	0.878
19:54773517:C:G	F85L	0.878
19:54773425:T:C	F55L	0.871
19:54773427:T:A	F55L	0.871
19:54773427:T:G	F55L	0.871
19:54775386:T:A	C198S	0.870
19:54775387:G:C	C198S	0.870

dbSNP variants (sampled 300 via entrez): RS1000067648 (19:54774776 T>A,G), RS1000973765 (19:54847209 G>A,T), RS1000990420 (19:54772772 C>G,T), RS1001062397 (19:54772143 G>A,C,T), RS1001149346 (19:54782731 T>G), RS1001479341 (19:54847003 G>A,T), RS1001576466 (19:54841191 T>C), RS1001581690 (19:54768643 G>A), RS1001663811 (19:54778142 T>A,C,G), RS1002011191 (19:54768276 TA>T), RS1002227919 (19:54784309 C>T), RS1002710694 (19:54837307 A>G,T), RS1002905831 (19:54837226 G>A,T), RS1003339707 (19:54781009 A>C,G), RS1003413396 (19:54780508 T>C)

Disease associations

OMIM: gene MIM:604952 | 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

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

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

Clinical trials (associated diseases)

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