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   17-JUN-2020, entry version 124.
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   SMR; Q6UVW9; -.
DR   DIP; DIP-58611N; -.
DR   IntAct; Q6UVW9; 6.
DR   STRING; 9606.ENSP00000396163; -.
DR   MEROPS; I63.002; -.
DR   iPTMnet; Q6UVW9; -.
DR   BioMuta; CLEC2A; -.
DR   DMDM; 212276429; -.
DR   PaxDb; Q6UVW9; -.
DR   PeptideAtlas; Q6UVW9; -.
DR   PRIDE; Q6UVW9; -.
DR   ProteomicsDB; 67436; -. [Q6UVW9-1]
DR   ProteomicsDB; 67437; -. [Q6UVW9-2]
DR   TopDownProteomics; Q6UVW9-1; -. [Q6UVW9-1]
DR   Antibodypedia; 53022; 153 antibodies.
DR   Ensembl; ENST00000339766; ENSP00000339732; ENSG00000188393. [Q6UVW9-2]
DR   Ensembl; ENST00000455827; ENSP00000396163; ENSG00000188393. [Q6UVW9-1]
DR   GeneID; 387836; -.
DR   KEGG; hsa:387836; -.
DR   UCSC; uc009zhb.3; human. [Q6UVW9-1]
DR   CTD; 387836; -.
DR   DisGeNET; 387836; -.
DR   EuPathDB; HostDB:ENSG00000188393.8; -.
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   eggNOG; KOG4297; Eukaryota.
DR   eggNOG; ENOG410XPJ1; LUCA.
DR   GeneTree; ENSGT00940000163789; -.
DR   HOGENOM; CLU_049894_8_4_1; -.
DR   InParanoid; Q6UVW9; -.
DR   KO; K22680; -.
DR   OMA; FNDWFEI; -.
DR   OrthoDB; 1289964at2759; -.
DR   PhylomeDB; Q6UVW9; -.
DR   TreeFam; TF351467; -.
DR   BioGRID-ORCS; 387836; 1 hit in 780 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 33 other tissues.
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; Polymorphism; 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:0000244|PDB:4IOP"
FT   STRAND          68..72
FT                   /evidence="ECO:0000244|PDB:4IOP"
FT   HELIX           79..87
FT                   /evidence="ECO:0000244|PDB:4IOP"
FT   TURN            88..90
FT                   /evidence="ECO:0000244|PDB:4IOP"
FT   HELIX           99..107
FT                   /evidence="ECO:0000244|PDB:4IOP"
FT   TURN            108..111
FT                   /evidence="ECO:0000244|PDB:4IOP"
FT   STRAND          114..121
FT                   /evidence="ECO:0000244|PDB:4IOP"
FT   STRAND          129..131
FT                   /evidence="ECO:0000244|PDB:4IOP"
FT   STRAND          143..149
FT                   /evidence="ECO:0000244|PDB:4IOP"
FT   STRAND          154..157
FT                   /evidence="ECO:0000244|PDB:4IOP"
FT   STRAND          163..170
FT                   /evidence="ECO:0000244|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
//