CLC2A_HUMAN
ID CLC2A_HUMAN Reviewed; 174 AA.
AC Q6UVW9; A5Y4G5; A9QKS2; A9QKS3;
DT 12-DEC-2006, integrated into UniProtKB/Swiss-Prot.
DT 04-NOV-2008, sequence version 2.
DT 03-AUG-2022, entry version 134.
DE RecName: Full=C-type lectin domain family 2 member A;
DE AltName: Full=Keratinocyte-associated C-type lectin;
DE Short=KACL;
DE AltName: Full=Proliferation-induced lymphocyte-associated receptor;
DE Short=PILAR;
GN Name=CLEC2A; Synonyms=KACL; ORFNames=UNQ5792/PRO19597;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, INTERACTION WITH KLRB1,
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RC TISSUE=Spleen;
RX PubMed=18550855; DOI=10.1182/blood-2007-12-130773;
RA Huarte E., Cubillos-Ruiz J.R., Nesbeth Y.C., Scarlett U.K., Martinez D.G.,
RA Engle X.A., Rigby W.F., Pioli P.A., Guyre P.M., Conejo-Garcia J.R.;
RT "PILAR is a novel modulator of human T-cell expansion.";
RL Blood 112:1259-1268(2008).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT identify novel human secreted and transmembrane proteins: a bioinformatics
RT assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 8-166 (ISOFORM 1), NUCLEOTIDE SEQUENCE [MRNA]
RP OF 8-154 (ISOFORM 2), VARIANT ASP-136, SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Histiocytic lymphoma;
RX PubMed=18046548; DOI=10.1007/s00251-007-0263-1;
RA Spreu J., Kienle E.C., Schrage B., Steinle A.;
RT "CLEC2A: a novel, alternatively spliced and skin-associated member of the
RT NKC-encoded AICL-CD69-LLT1 family.";
RL Immunogenetics 59:903-912(2007).
RN [4]
RP FUNCTION, SUBUNIT, GLYCOSYLATION, AND TISSUE SPECIFICITY.
RX PubMed=20194751; DOI=10.1073/pnas.0913108107;
RA Spreu J., Kuttruff S., Stejfova V., Dennehy K.M., Schittek B., Steinle A.;
RT "Interaction of C-type lectin-like receptors NKp65 and KACL facilitates
RT dedicated immune recognition of human keratinocytes.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:5100-5105(2010).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (3.2 ANGSTROMS) OF 46-174 IN COMPLEX WITH KLRF2,
RP SUBUNIT, INTERACTION WITH KLRF2, MUTAGENESIS OF PHE-148; ASP-152; HIS-155;
RP 157-SER-ARG-158 AND ASP-162, GLYCOSYLATION AT ASN-78 AND ASN-130, AND
RP DISULFIDE BOND.
RX PubMed=23803857; DOI=10.1073/pnas.1303300110;
RA Li Y., Wang Q., Chen S., Brown P.H., Mariuzza R.A.;
RT "Structure of NKp65 bound to its keratinocyte ligand reveals basis for
RT genetically linked recognition in natural killer gene complex.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:11505-11510(2013).
CC -!- FUNCTION: Plays a role in modulating the extent of T-cell expansion.
CC Enhances the expansion of TCR-stimulated T-cells by increasing their
CC survival through enhanced expression of anti-apoptotic proteins. May
CC modulate the capacity of T-cells to home to lymph nodes through SELL.
CC Facilitates dedicated immune recognition of keratinocytes via
CC interaction with its receptor KLRF2 by stimulating natural killer cell
CC mediated cytotoxicity. {ECO:0000269|PubMed:18550855,
CC ECO:0000269|PubMed:20194751}.
CC -!- SUBUNIT: Homodimer; non disulfide-linked. Interacts with KLRB1.
CC Interacts with KLRF2. {ECO:0000269|PubMed:18550855,
CC ECO:0000269|PubMed:20194751, ECO:0000269|PubMed:23803857}.
CC -!- INTERACTION:
CC Q6UVW9; Q9UHP7-3: CLEC2D; NbExp=3; IntAct=EBI-15839595, EBI-11749983;
CC Q6UVW9; O60883: GPR37L1; NbExp=3; IntAct=EBI-15839595, EBI-2927498;
CC Q6UVW9; Q8TED1: GPX8; NbExp=3; IntAct=EBI-15839595, EBI-11721746;
CC Q6UVW9; P31937: HIBADH; NbExp=3; IntAct=EBI-15839595, EBI-11427100;
CC Q6UVW9; Q8N6K0: TEX29; NbExp=3; IntAct=EBI-15839595, EBI-19027521;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:18046548,
CC ECO:0000269|PubMed:18550855}; Single-pass type II membrane protein
CC {ECO:0000269|PubMed:18046548, ECO:0000269|PubMed:18550855}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=CLEC2A1;
CC IsoId=Q6UVW9-1; Sequence=Displayed;
CC Name=2; Synonyms=CLEC2A2;
CC IsoId=Q6UVW9-2; Sequence=VSP_035643;
CC -!- TISSUE SPECIFICITY: Mainly expressed in skin. Also expressed in
CC keratinocytes, spleen, thymus, small intestine, peripheral blood
CC monocytes, bone marrow, ovary, testis and skin. High expression in
CC CD8(+), B-lymphocytes and naive CD4(+) T-cells. Restricted mostly to
CC proliferating lymphocytes. Not detected in myeloid leukocytes or
CC natural killer (NK) cells. {ECO:0000269|PubMed:18046548,
CC ECO:0000269|PubMed:18550855, ECO:0000269|PubMed:20194751}.
CC -!- INDUCTION: By phytohemagglutinin (PHA) in peripheral CD8(+) T cells.
CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:20194751,
CC ECO:0000269|PubMed:23803857}.
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DR EMBL; EF127467; ABO33172.1; -; mRNA.
DR EMBL; AY359126; AAQ89483.1; -; mRNA.
DR EMBL; EU095393; ABW79912.1; -; mRNA.
DR EMBL; EU095394; ABW79913.1; -; mRNA.
DR CCDS; CCDS44829.1; -. [Q6UVW9-1]
DR CCDS; CCDS8606.1; -. [Q6UVW9-2]
DR RefSeq; NP_001124183.1; NM_001130711.1. [Q6UVW9-1]
DR RefSeq; NP_997258.1; NM_207375.2. [Q6UVW9-2]
DR PDB; 4IOP; X-ray; 3.20 A; A=46-174.
DR PDBsum; 4IOP; -.
DR AlphaFoldDB; Q6UVW9; -.
DR SMR; Q6UVW9; -.
DR BioGRID; 132462; 5.
DR DIP; DIP-58611N; -.
DR IntAct; Q6UVW9; 6.
DR STRING; 9606.ENSP00000396163; -.
DR MEROPS; I63.002; -.
DR GlyGen; Q6UVW9; 3 sites.
DR iPTMnet; Q6UVW9; -.
DR BioMuta; CLEC2A; -.
DR DMDM; 212276429; -.
DR MassIVE; Q6UVW9; -.
DR PaxDb; Q6UVW9; -.
DR PeptideAtlas; Q6UVW9; -.
DR PRIDE; Q6UVW9; -.
DR TopDownProteomics; Q6UVW9-1; -. [Q6UVW9-1]
DR Antibodypedia; 53022; 158 antibodies from 23 providers.
DR DNASU; 387836; -.
DR Ensembl; ENST00000339766.8; ENSP00000339732.4; ENSG00000188393.9. [Q6UVW9-2]
DR Ensembl; ENST00000455827.2; ENSP00000396163.1; ENSG00000188393.9. [Q6UVW9-1]
DR GeneID; 387836; -.
DR KEGG; hsa:387836; -.
DR MANE-Select; ENST00000455827.2; ENSP00000396163.1; NM_001130711.2; NP_001124183.1.
DR UCSC; uc009zhb.3; human. [Q6UVW9-1]
DR CTD; 387836; -.
DR DisGeNET; 387836; -.
DR GeneCards; CLEC2A; -.
DR HGNC; HGNC:24191; CLEC2A.
DR HPA; ENSG00000188393; Tissue enriched (skin).
DR MIM; 612087; gene.
DR neXtProt; NX_Q6UVW9; -.
DR OpenTargets; ENSG00000188393; -.
DR PharmGKB; PA142672099; -.
DR VEuPathDB; HostDB:ENSG00000188393; -.
DR eggNOG; KOG4297; Eukaryota.
DR GeneTree; ENSGT00940000163789; -.
DR HOGENOM; CLU_049894_8_4_1; -.
DR InParanoid; Q6UVW9; -.
DR OMA; FNDWFEI; -.
DR OrthoDB; 1289964at2759; -.
DR PhylomeDB; Q6UVW9; -.
DR TreeFam; TF351467; -.
DR PathwayCommons; Q6UVW9; -.
DR SignaLink; Q6UVW9; -.
DR BioGRID-ORCS; 387836; 4 hits in 1052 CRISPR screens.
DR GenomeRNAi; 387836; -.
DR Pharos; Q6UVW9; Tbio.
DR PRO; PR:Q6UVW9; -.
DR Proteomes; UP000005640; Chromosome 12.
DR RNAct; Q6UVW9; protein.
DR Bgee; ENSG00000188393; Expressed in skin of leg and 42 other tissues.
DR GO; GO:0009897; C:external side of plasma membrane; IBA:GO_Central.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0030246; F:carbohydrate binding; IEA:UniProtKB-KW.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0042267; P:natural killer cell mediated cytotoxicity; TAS:UniProtKB.
DR CDD; cd03593; CLECT_NK_receptors_like; 1.
DR Gene3D; 3.10.100.10; -; 1.
DR InterPro; IPR001304; C-type_lectin-like.
DR InterPro; IPR016186; C-type_lectin-like/link_sf.
DR InterPro; IPR016187; CTDL_fold.
DR InterPro; IPR033992; NKR-like_CTLD.
DR Pfam; PF00059; Lectin_C; 1.
DR SMART; SM00034; CLECT; 1.
DR SUPFAM; SSF56436; SSF56436; 1.
DR PROSITE; PS50041; C_TYPE_LECTIN_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Disulfide bond;
KW Glycoprotein; Lectin; Membrane; Receptor; Reference proteome;
KW Signal-anchor; Transmembrane; Transmembrane helix.
FT CHAIN 1..174
FT /note="C-type lectin domain family 2 member A"
FT /id="PRO_0000264240"
FT TOPO_DOM 1..27
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 28..48
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 49..174
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT DOMAIN 65..174
FT /note="C-type lectin"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00040"
FT CARBOHYD 78
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:23803857"
FT CARBOHYD 130
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:23803857"
FT CARBOHYD 143
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 58..69
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00040,
FT ECO:0000269|PubMed:23803857"
FT DISULFID 86..167
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00040,
FT ECO:0000269|PubMed:23803857"
FT VAR_SEQ 138..174
FT /note="FEIIGNGSFAFLSADGVHSSRGFIDIKWICSKPKYFL -> PSNSKWSCNWS
FT LRQWLLLLGPLR (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:12975309,
FT ECO:0000303|PubMed:18046548"
FT /id="VSP_035643"
FT VARIANT 136
FT /note="G -> D (in dbSNP:rs526680)"
FT /evidence="ECO:0000269|PubMed:18046548"
FT /id="VAR_029629"
FT MUTAGEN 148
FT /note="F->A: Reduces affinity for KLRF2 40-fold."
FT /evidence="ECO:0000269|PubMed:23803857"
FT MUTAGEN 152
FT /note="D->A: No effect on affinity for KLRF2."
FT /evidence="ECO:0000269|PubMed:23803857"
FT MUTAGEN 155
FT /note="H->A: Slightly reduces affinity for KLRF2."
FT /evidence="ECO:0000269|PubMed:23803857"
FT MUTAGEN 157..158
FT /note="SR->AA: Reduces affinity for KLRF2 over 10'000-
FT fold."
FT /evidence="ECO:0000269|PubMed:23803857"
FT MUTAGEN 160..161
FT /note="FI->AA: Reduces affinity for KLRF2 550-fold."
FT MUTAGEN 162
FT /note="D->A: Reduces affinity for KLRF2 360-fold."
FT /evidence="ECO:0000269|PubMed:23803857"
FT STRAND 60..65
FT /evidence="ECO:0007829|PDB:4IOP"
FT STRAND 68..72
FT /evidence="ECO:0007829|PDB:4IOP"
FT HELIX 79..87
FT /evidence="ECO:0007829|PDB:4IOP"
FT TURN 88..90
FT /evidence="ECO:0007829|PDB:4IOP"
FT HELIX 99..107
FT /evidence="ECO:0007829|PDB:4IOP"
FT TURN 108..111
FT /evidence="ECO:0007829|PDB:4IOP"
FT STRAND 114..121
FT /evidence="ECO:0007829|PDB:4IOP"
FT STRAND 129..131
FT /evidence="ECO:0007829|PDB:4IOP"
FT STRAND 143..149
FT /evidence="ECO:0007829|PDB:4IOP"
FT STRAND 154..157
FT /evidence="ECO:0007829|PDB:4IOP"
FT STRAND 163..170
FT /evidence="ECO:0007829|PDB:4IOP"
SQ SEQUENCE 174 AA; 19972 MW; 76E137A5053361B9 CRC64;
MINPELRDGR ADGFIHRIVP KLIQNWKIGL MCFLSIIITT VCIIMIATWS KHAKPVACSG
DWLGVRDKCF YFSDDTRNWT ASKIFCSLQK AELAQIDTQE DMEFLKRYAG TDMHWIGLSR
KQGDSWKWTN GTTFNGWFEI IGNGSFAFLS ADGVHSSRGF IDIKWICSKP KYFL
