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Abstract

Abstract KLRK1 encodes a type II transmembrane-anchored glycoprotein that is expressed as a disulfide-linked homodimer on the surface of Natural Killer (NK) cells, gamma/delta TcR+ T cells, CD8+ T cells, and a minor subset of CD4+ T cells. It associates non-covalently with the DAP10 signaling protein and provides activating or costimulatory signals to NK cells and T cells. NKG2D binds to a family of glycoproteins, in humans the MICA, MICB, and ULBP1-6 membrane proteins, which are frequently expressed on cells that have become infected with pathogens or undergone transformation.

KLRK1 (killer cell lectin-like receptor subfamily K, member 1)

Identity

Other namesD12S2489E
CD314
KLR
NKG2-D
NKG2D
HGNC (Hugo) KLRK1
LocusID (NCBI) 22914
Location 12p13.2
Location_base_pair Starts at 10524952 and ends at 10542653 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

Note KLRK1 is present on chromosome 12 within a cluster of genes referred to as the "NK complex" (NKC) because several genes that are preferentially expressed by Natural Killer (NK) cells are located in this region, including on the centromeric side KLRD1 (CD94) and on the telomeric side KLRC4 (NKG2F), KLRC3 (NKG2E), KLRC2 (NKG2C), and KLRC1 (NKG2A) (Houchins et al., 1991).
 
  Schematic representation of the KLRC2 (NKG2C), KLR3 (NKG2E), KLRC4 (NKG2F), and KLRK1 genes on human chromosome 12p13.2 (taken from Glienke et al., 1998, figure 4).
Description The KLRK1 gene is 17702 bases located on the negative strand of chromosome 12 spanning bases 10372353 to 103900054 with a predicted 7 exons.
Transcription There is evidence for alternative splicing of KLRK1, but only one isoform encoding a functional protein has been described in humans. In one of the KLRK1 splice variants the fourth exon of KLRC4 is spliced to the 5-prime end of KLRK1. KLRK1 is transcribed by NK cells, gamma/delta-TcR+ T cells, CD8+ T cells and some CD4+ T cells (Bauer et al., 1999). Transcription of KLRK1 is enhanced by stimulation of NK cells with IL-2 or IL-15 and decreased by culture with TGF-beta.
Pseudogene No known pseudogenes.

Protein

Note KLRK1 is a type II transmembrane-anchored membrane glycoprotein expressed as a disulfide-bonded homodimer on the cell surface. Expression of KLRK1 on the cell surface requires its association with DAP10, which is a type I adapter protein expressed as a disulfide-bonded homodimer (Wu et al., 1999). On the cell surface, the receptor complex is a hexamer; two disulfide-bonded KLRK1 homodimers each paired with two DAP10 disulfide-bonded homodimers (Garrity et al., 2005). A charged amino acid residue (aspartic acid) centrally located within the transmembrane region of DAP10 forms a salt bridge with a charged amino acid residue (arginine) in the transmembrane region of KLRK1 to stabilize the receptor complex (Wu et al., 1999).
 
  Amino acid sequence of KLRK1 is shown, with the predicted transmembrane domain underlined. The R residue in the transmembrane is required for association of KLRK1 with the DAP10 signaling protein to form the mature receptor complex. Three potential sites for N-linked glycosylation are in bold.
Description KLRK1 is a type II membrane protein comprising 216 amino acids with a predicted molecular weight of 25,143 kDa. The protein has an N-terminal intracellular region, a transmembrane domain, a membrane-proximal stalk region, and an extracellular region with a single C-type lectin-like domain. KLRK1 is expressed on the cell surface as a disulfide-bonded homodimer with a molecular weight of approximately 42 kDa when analyzed under reducing conditions and approximately 80 kDa under non-reducing conditions. A cysteine residue just outside the transmembrane region forms the disulfide bond joining the two subunits of the homodimer. There are three potential sites for N-linked glycosylation in the extracellular region of KLRK1. Treatment of the KLRK1 glycoprotein with N-glycanase reduces the molecular weight to approximately the size of the core polypeptide.
 
  Schematic representation of the KLRK1 (NKG2D) - DAP10 receptor complex (taken from Garrity et al., 2005, figure 7).
Expression KLRK1 protein is expressed on the cell surface of NK cells, gamma/delta-TcR+ T cells, CD8+ T cells, and some CD4+ T cells (Bauer et al., 1999).
Localisation KLRK1 is expressed as a type II integral membrane glycoprotein on the cell surface of NK cells, gamma/delta-TcR+ T cells, CD8+ T cells, and some CD4+ T cells (Bauer et al., 1999). In the absence of DAP10, KLRK1 protein is retained in the cytoplasm and degraded (Wu et al., 1999).
Function KLRK1 binds to at least eight distinct ligands: MICA, MICB, ULBP-1, ULBP-2, ULBP-3, ULBP-4, ULBP-5, and ULBP-6 (Bauer et al., 1999; Cosman et al., 2001; Raulet et al., 2013). These ligands are type I glycoproteins with homology to MHC class I. The KLRK1 ligands frequently are over-expressed on tumor cells, virus-infected cells, and "stressed" cells (Raulet et al., 2013). The crystal structure of KLRK1 bound to MICA has been described (Li et al., 2001). After binding to its ligand, KLRK1 transmits an activating signal via the DAP10 adapter subunit. DAP10 has a YINM motif in its cytoplasmic domain, which upon tyrosine phosphorylation binds to Vav and the p85 subunit of PI3-kinase (Billadeau et al., 2003; Wu et al., 1999), causing a downstream cascade of signaling in T cells and NK cells, resulting in the killing of ligand-bearing cells and the secretion of cytokines by NK cells and T cells.
 
  Structure of the KLRK1 homodimer (a) and its ligand MICA (b) (taken from Li et al., 2001, figure 1).
Homology Pan troglodytes: NP_001009059
Macaca mulatta: NP_001028061
Macaca fascicularis: CAD19993
Callithrix jacchus: ABN45890
Papio anubis: ABO09749
Pongo pygmaeus: Q8MJH1
Bos taurus: CAJ27114
Sus scrofa: Q9GLF5
Mus musculus: NP_149069
Mus musculus: NP_001076791
Rattus norvegicus: NP_598196
Callithrix jacchus: A4GHD0
Neovison vison: U6DVF4
Microcebus murinus: D1GEY1
Varecia variegate: D1GF00
Lithobates catesbeiana: C1C4X9

Mutations

Note None identified.

Implicated in

Entity Cancer
Note Many types of cancer (carcinomas, sarcomas, lymphomas, and leukemias) over-express the ligands for KLRK1 (Raulet et al., 2013). In some cases, this renders the tumor cells susceptible to killing by activated KLRK1-bearing NK cells. Some tumors shed or secrete soluble ligands that bind to KLRK1, which downregulates expression of KLRK1 on NK cells and T cells (Groh et al., 2002), although the physiological relevance of the shed ligands is controversial. Mice in which the Klrk1 gene has been disrupted show increased susceptibility to certain cancers caused by transgenic expression of oncogenes (Guerra et al., 2008).
  
Entity Viral infection
Note Viral infection of cells can induce transcription and cell surface expression of ligands for KLRK1, rendering these infected cells susceptible to attack by NK cells and T cells (Champsaur and Lanier, 2010; Raulet et al., 2013). Some viruses, for example cytomegalovirus, encode proteins that intercept the ligand proteins intracellularly and prevent their expression on the surface of virus-infected cells.
  
Entity Rheumatoid arthritis
Note An expansion of CD4+,CD28- T cells expressing KLRK1 was observed in the joints of patients with rheumatoid arthritis and KLRK1 ligands were detected on synovial cells in the inflamed tissue (Groh et al., 2003).
  
Entity Type I diabetes
Note Peripheral blood NK cells and T cells in patients with type I diabetes demonstrate a slightly decreased amount of expression of KLRK1 on the cell surface, independent disease duration (Rodacki et al., 2007), similar to prior observations in the NOD mouse (Ogasawara et al., 2003).
  

External links

Nomenclature
HGNC (Hugo)KLRK1   18788
Cards
AtlasKLRK1ID41094ch12p13
Entrez_Gene (NCBI)KLRK1  22914  killer cell lectin-like receptor subfamily K, member 1
GeneCards (Weizmann)KLRK1
Ensembl hg19 (Hinxton)ENSG00000213809 [Gene_View]  chr12:10524952-10542653 [Contig_View]  KLRK1 [Vega]
Ensembl hg38 (Hinxton)ENSG00000213809 [Gene_View]  chr12:10524952-10542653 [Contig_View]  KLRK1 [Vega]
ICGC DataPortalENSG00000213809
cBioPortalKLRK1
AceView (NCBI)KLRK1
Genatlas (Paris)KLRK1
WikiGenes22914
SOURCE (Princeton)KLRK1
Genomic and cartography
GoldenPath hg19 (UCSC)KLRK1  -     chr12:10524952-10542653 -  12p13.2-p12.3   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)KLRK1  -     12p13.2-p12.3   [Description]    (hg38-Dec_2013)
EnsemblKLRK1 - 12p13.2-p12.3 [CytoView hg19]  KLRK1 - 12p13.2-p12.3 [CytoView hg38]
Mapping of homologs : NCBIKLRK1 [Mapview hg19]  KLRK1 [Mapview hg38]
OMIM611817   
Gene and transcription
Genbank (Entrez)AF260135 AF260136 AK226161 AK292059 BC039836
RefSeq transcript (Entrez)NM_007360
RefSeq genomic (Entrez)AC_000144 NC_000012 NC_018923 NG_027762 NT_009714 NW_001838052 NW_004929383
Consensus coding sequences : CCDS (NCBI)KLRK1
Cluster EST : UnigeneHs.387787 [ NCBI ]
CGAP (NCI)Hs.387787
Alternative Splicing : Fast-db (Paris)GSHG0007251
Alternative Splicing GalleryENSG00000213809
Gene ExpressionKLRK1 [ NCBI-GEO ]     KLRK1 [ SEEK ]   KLRK1 [ MEM ]
SOURCE (Princeton)Expression in : [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP26718 (Uniprot)
NextProtP26718  [Medical]
With graphics : InterProP26718
Splice isoforms : SwissVarP26718 (Swissvar)
Domaine pattern : Prosite (Expaxy)C_TYPE_LECTIN_2 (PS50041)   
Domains : Interpro (EBI)C-type_lectin    C-type_lectin-like    C-type_lectin_fold   
Related proteins : CluSTrP26718
Domain families : Pfam (Sanger)Lectin_C (PF00059)   
Domain families : Pfam (NCBI)pfam00059   
Domain families : Smart (EMBL)CLECT (SM00034)  
DMDM Disease mutations22914
Blocks (Seattle)P26718
PDB (SRS)1HYR    1KCG    1MPU   
PDB (PDBSum)1HYR    1KCG    1MPU   
PDB (IMB)1HYR    1KCG    1MPU   
PDB (RSDB)1HYR    1KCG    1MPU   
Human Protein AtlasENSG00000213809
Peptide AtlasP26718
HPRD17240
Protein Interaction databases
DIP (DOE-UCLA)P26718
IntAct (EBI)P26718
FunCoupENSG00000213809
BioGRIDKLRK1
IntegromeDBKLRK1
STRING (EMBL)KLRK1
Ontologies - Pathways
QuickGOP26718
Ontology : AmiGO
Ontology : EGO-EBI
Pathways : KEGGNatural killer cell mediated cytotoxicity    Malaria   
REACTOMEP26718 [protein]
REACTOME PathwaysREACT_6900 Immune System [pathway]
Protein Interaction DatabaseKLRK1
DoCM (Curated mutations)KLRK1
Wikipedia pathwaysKLRK1
Gene fusion - rearrangements
Polymorphisms : SNP, variants
NCBI Variation ViewerKLRK1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)KLRK1
dbVarKLRK1
ClinVarKLRK1
1000_GenomesKLRK1 
Exome Variant ServerKLRK1
SNP (GeneSNP Utah)KLRK1
SNP : HGBaseKLRK1
Genetic variants : HAPMAPKLRK1
Genomic VariantsKLRK1  KLRK1 [DGVbeta]
Mutations
ICGC Data PortalENSG00000213809 
Somatic Mutations in Cancer : COSMICKLRK1 
CONAN: Copy Number AnalysisKLRK1 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
Diseases
DECIPHER (Syndromes)12:10524952-10542653
Mutations and Diseases : HGMDKLRK1
OMIM611817   
MedgenKLRK1
NextProtP26718 [Medical]
GENETestsKLRK1
Disease Genetic AssociationKLRK1
Huge Navigator KLRK1 [HugePedia]  KLRK1 [HugeCancerGEM]
snp3D : Map Gene to Disease22914
DGIdb (Drug Gene Interaction db)KLRK1
General knowledge
Homologs : HomoloGeneKLRK1
Homology/Alignments : Family Browser (UCSC)KLRK1
Phylogenetic Trees/Animal Genes : TreeFamKLRK1
Chemical/Protein Interactions : CTD22914
Chemical/Pharm GKB GenePA128394594
Clinical trialKLRK1
Cancer Resource (Charite)ENSG00000213809
Other databases
Probes
Litterature
PubMed241 Pubmed reference(s) in Entrez
CoreMineKLRK1
GoPubMedKLRK1
iHOPKLRK1

Bibliography

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PMID 11239445
 
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Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis.
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PMID 12878725
 
Impairment of NK cell function by NKG2D modulation in NOD mice.
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PMID 12530974
 
The activating NKG2D receptor assembles in the membrane with two signaling dimers into a hexameric structure.
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PMID 15894612
 
Altered natural killer cells in type 1 diabetic patients.
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PMID 17192480
 
NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy.
Guerra N, Tan YX, Joncker NT, Choy A, Gallardo F, Xiong N, Knoblaugh S, Cado D, Greenberg NM, Raulet DH.
Immunity. 2008 Apr;28(4):571-80. doi: 10.1016/j.immuni.2008.02.016.
PMID 18394936
 
Effect of NKG2D ligand expression on host immune responses.
Champsaur M, Lanier LL.
Immunol Rev. 2010 May;235(1):267-85. doi: 10.1111/j.0105-2896.2010.00893.x. (REVIEW)
PMID 20536569
 
Regulation of ligands for the NKG2D activating receptor.
Raulet DH, Gasser S, Gowen BG, Deng W, Jung H.
Annu Rev Immunol. 2013;31:413-41. doi: 10.1146/annurev-immunol-032712-095951. Epub 2013 Jan 3. (REVIEW)
PMID 23298206
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written07-2007Lewis L Lanier
UCSF, Department of Microbiology and Immunology, San Francisco, CA 94143-0414, USA
Updated06-2014Lewis L Lanier
UCSF, Department of Microbiology and Immunology, San Francisco, CA 94143-0414, USA

Citation

This paper should be referenced as such :
Lanier LL
KLRK1 (killer cell lectin-like receptor subfamily K, member 1);
Atlas Genet Cytogenet Oncol Haematol. June 2014
Free online version   Free pdf version   [Bibliographic record ]
Atlas Genet Cytogenet Oncol Haematol. June 2014
URL : http://AtlasGeneticsOncology.org/Genes/KLRK1ID41094ch12p13.html

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