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

Identity

Other namesCD314
D12S2489E
NKG2D
NKG2-D
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]
Local_order KLRK1 is flanked by KLRD1 (CD94) on the centromeric and KLRC4 (NKG2F) on the telomeric side. The 3' end of the KLRC4 transcript includes the first non-coding exon found at the 5' end of the adjacent KLRK1 gene transcript.
Note KLRK1 is on chromosome 12p13.2-p12.3 at 10,416,857-10,454,012. KLRK1 is a member of the C-type lectin-like family of type II cell surface glycoproteins. It is expressed by NK cells, CD8+ T cells, gamma/delta-TcR+ T cells, and a minor subset of CD4+ T cells. KLRK1 associates with the DAP10 transmembrane adapter protein and transmits activating signalings into these lymphocytes.

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 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).
Description The KLRK1 gene is 37,793 bases located on the negative strand of chromosome 12 spanning 10,416,219 to 10,454,012 bp. ENTREZ database predicts 12 exons.
Three alleles of KLRK1 differing by substitutions at only two nucleotide positions, of which one is nonsynonymous and the other synonymous, have been reported.
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.
Transcription of KLRK1 is enhanced by stimulation of NK cells with IL-2 or IL-15 and decreased by culture with TGF-beta.

Protein

Note KLRK1 is a type II 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. On the cell surface, the receptor complex is a hexamer; two disulfide-bonded KLRK1/NKG2D homodimers each paired with two DAP10 disulfide-bonded homodimers. 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/NKG2D to stabilize the receptor complex.
Description KLRK1 is a type II membrane protein comprising 216 amino acids with a predicted molecular weight of 25143 kD. The protein has an N-terminal intracellular region, a transmembrane domain, and a C-terminal 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 kd when analyzed under reducing conditions and approximately 80 kd 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. 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.
Expression KLRK1 is transcribed by NK cells, gamma/delta-TcR+ T cells, CD8+ T cells and some CD4+ T cells.
Localisation KLRK1 is expressed as a type II glycoprotein on the cell surface of NK cells, gamma/delta-TcR+ T cells, CD8+ T cells and some CD4+ T cells.
Function KLRK1 binds to at least seven distinct ligands: MICA, MICB, ULBP-1, ULBP-2, ULBP-3, ULBP-4, and RAET1G. These ligands are type I glycoproteins with homology to MHC class I.
The KLRK1 ligand are frequently over-expressed on tumor cells, virus-infected cells, and "stressed" cells.
The crystal structure of KLRK1 bound to MICA has been reported. After binding to its ligand, KLRK1 transmits an activating signal via the DAP10 adapter subunit.
DAP10 has a YxxM motif in its cytoplasmic domain, which upon tyrosine phosphorylation binds to Vav and the p85 subunit of PI3-kinase, causing a downstream cascade of signaling in T cells and NK cells.
Homology NKG2-D type II integral membrane protein [Pan troglodytes] NP_001009059
NKG2D protein [Macaca mulatta] NP_001028061
NKG2D receptor [Macaca fascicularis] CAD19993
NKG2D [Callithrix jacchus] ABN45890
NKG2D [Papio anubis] ABO09749
NKG2-D type II integral membrane protein [Pongo pygmaeus] Q8MJH1
putative immunoreceptor NKG2D [Bos taurus] CAJ27114
NKG2-D type II integral membrane protein [Sus scrofa] Q9GLF5
NKG2-D isoform a [Mus musculus] NP_149069
NKG2-D isoform b [Mus musculus] NP_001076791
killer cell lectin-like receptor subfamily K, member 1 [Rattus norvegicus] NP_598196

Mutations

Note None identified.

Implicated in

Entity Cancer
Note Many types of cancer (carcinomas, sarcomas, lymphomas, leukemias) over-express the ligands for KLRK1. 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 and down-regulate expression of the KLRK1 receptor on NK cells and T cells, potentially to evade attack by these immune effector cells.
  
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. Some viruses, for example cytomegalovirus, encodes 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.
  
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, similar to prior observations in the NOD mouse.
  

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 (Hinxton)ENSG00000213809 [Gene_View]  chr12:10524952-10542653 [Contig_View]  KLRK1 [Vega]
ICGC DataPortalENSG00000213809
cBioPortalKLRK1
AceView (NCBI)KLRK1
Genatlas (Paris)KLRK1
WikiGenes22914
SOURCE (Princeton)NM_007360
Genomic and cartography
GoldenPath (UCSC)KLRK1  -  12p13.2   chr12:10524952-10542653 -  12p13.2-p12.3   [Description]    (hg19-Feb_2009)
EnsemblKLRK1 - 12p13.2-p12.3 [CytoView]
Mapping of homologs : NCBIKLRK1 [Mapview]
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 ]
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 [organisation]   C-type_lectin-like [organisation]   C-type_lectin_fold [organisation]  
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 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasP26718
HPRD17240
Protein Interaction databases
DIP (DOE-UCLA)P26718
IntAct (EBI)P26718
FunCoupENSG00000213809
BioGRIDKLRK1
InParanoidP26718
Interologous Interaction database P26718
IntegromeDBKLRK1
STRING (EMBL)KLRK1
Ontologies - Pathways
Ontology : AmiGO
Ontology : EGO-EBI
Pathways : KEGGNatural killer cell mediated cytotoxicity    Malaria   
Protein Interaction DatabaseKLRK1
Wikipedia pathwaysKLRK1
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)KLRK1
snp3D : Map Gene to Disease22914
SNP (GeneSNP Utah)KLRK1
SNP : HGBaseKLRK1
Genetic variants : HAPMAPKLRK1
Exome VariantKLRK1
1000_GenomesKLRK1 
ICGC programENSG00000213809 
Somatic Mutations in Cancer : COSMICKLRK1 
CONAN: Copy Number AnalysisKLRK1 
Mutations and Diseases : HGMDKLRK1
Genomic VariantsKLRK1  KLRK1 [DGVbeta]
dbVarKLRK1
ClinVarKLRK1
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM611817   
MedgenKLRK1
GENETestsKLRK1
Disease Genetic AssociationKLRK1
Huge Navigator KLRK1 [HugePedia]  KLRK1 [HugeCancerGEM]
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
iHOPKLRK1
OncoSearchKLRK1

Bibliography

DNA sequence analysis of NKG2, a family of related cDNA clones encoding type II integral membrane proteins on human natural killer cells.
Houchins JP, Yabe T, McSherry C, Bach FH
The Journal of experimental medicine. 1991 ; 173 (4) : 1017-1020.
PMID 2007850
 
The genomic organization of NKG2C, E, F, and D receptor genes in the human natural killer gene complex.
Glienke J, Sobanov Y, Brostjan C, Steffens C, Nguyen C, Lehrach H, Hofer E, Francis F
Immunogenetics. 1998 ; 48 (3) : 163-173.
PMID 9683661
 
Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA.
Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, Spies T
Science (New York, N.Y.). 1999 ; 285 (5428) : 727-729.
PMID 10426993
 
A trigger of natural (and other) killers.
Hagmann M
Science (New York, N.Y.). 1999 ; 285 (5428) : page 645, 647.
PMID 10454908
 
ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor.
Cosman D, Mˆºllberg J, Sutherland CL, Chin W, Armitage R, Fanslow W, Kubin M, Chalupny NJ
Immunity. 2001 ; 14 (2) : 123-133.
PMID 11239445
 
Complex structure of the activating immunoreceptor NKG2D and its MHC class I-like ligand MICA.
Li P, Morris DL, Willcox BE, Steinle A, Spies T, Strong RK
Nature immunology. 2001 ; 2 (5) : 443-451.
PMID 11323699
 
Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation.
Groh V, Wu J, Yee C, Spies T
Nature. 2002 ; 419 (6908) : 734-738.
PMID 12384702
 
Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis.
Groh V, Bruhl A, El-Gabalawy H, Nelson JL, Spies T
Proceedings of the National Academy of Sciences of the United States of America. 2003 ; 100 (16) : 9452-9457.
PMID 12878725
 
The activating NKG2D receptor assembles in the membrane with two signaling dimers into a hexameric structure.
Garrity D, Call ME, Feng J, Wucherpfennig KW
Proceedings of the National Academy of Sciences of the United States of America. 2005 ; 102 (21) : 7641-7646.
PMID 15894612
 
Altered natural killer cells in type 1 diabetic patients.
Rodacki M, Svoren B, Butty V, Besse W, Laffel L, Benoist C, Mathis D
Diabetes. 2007 ; 56 (1) : 177-185.
PMID 17192480
 
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Contributor(s)

Written07-2007Lewis 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. 2008;12(1):47-49.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/KLRK1ID41094ch12p13.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Fri Aug 8 11:25:32 CEST 2014

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