CLC4D_HUMAN
ID CLC4D_HUMAN Reviewed; 215 AA.
AC Q8WXI8; Q8N5J5;
DT 15-FEB-2005, integrated into UniProtKB/Swiss-Prot.
DT 10-MAY-2005, sequence version 2.
DT 03-AUG-2022, entry version 148.
DE RecName: Full=C-type lectin domain family 4 member D;
DE AltName: Full=C-type lectin superfamily member 8;
DE AltName: Full=C-type lectin-like receptor 6;
DE Short=CLEC-6;
DE AltName: Full=Dendritic cell-associated C-type lectin 3 {ECO:0000303|PubMed:23911656};
DE Short=DC-associated C-type lectin 3 {ECO:0000303|PubMed:23911656};
DE Short=Dectin-3 {ECO:0000303|PubMed:23911656};
DE AltName: CD_antigen=CD368;
GN Name=CLEC4D {ECO:0000312|HGNC:HGNC:14554};
GN Synonyms=CLECSF8 {ECO:0000303|PubMed:14971047},
GN MCL {ECO:0000303|PubMed:23602766, ECO:0000303|PubMed:24101491};
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], FUNCTION, TISSUE SPECIFICITY, AND INDUCTION.
RX PubMed=14971047; DOI=10.1002/eji.200324230;
RA Arce I., Martinez-Munoz L., Roda-Navarro P., Fernandez-Ruiz E.;
RT "The human C-type lectin CLECSF8 is a novel monocyte/macrophage endocytic
RT receptor.";
RL Eur. J. Immunol. 34:210-220(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Macrophage;
RX PubMed=15368084; DOI=10.1007/s00251-004-0714-x;
RA Flornes L.M., Bryceson Y.T., Spurkland A., Lorentzen J.C., Dissen E.,
RA Fossum S.;
RT "Identification of lectin-like receptors expressed by antigen presenting
RT cells and neutrophils and their mapping to a novel gene complex.";
RL Immunogenetics 56:506-517(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT GLY-32.
RA Colonna M.;
RT "C-type lectin-like receptor.";
RL Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT GLY-32.
RC TISSUE=Peripheral blood;
RA Ma J., Liew C.-C.;
RL Submitted (MAY-2002) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Blood;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP FUNCTION.
RX PubMed=23602766; DOI=10.1016/j.immuni.2013.03.010;
RA Miyake Y., Toyonaga K., Mori D., Kakuta S., Hoshino Y., Oyamada A.,
RA Yamada H., Ono K., Suyama M., Iwakura Y., Yoshikai Y., Yamasaki S.;
RT "C-type lectin MCL is an FcRgamma-coupled receptor that mediates the
RT adjuvanticity of mycobacterial cord factor.";
RL Immunity 38:1050-1062(2013).
RN [7]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH CLEC6A.
RX PubMed=23911656; DOI=10.1016/j.immuni.2013.05.017;
RA Zhu L.L., Zhao X.Q., Jiang C., You Y., Chen X.P., Jiang Y.Y., Jia X.M.,
RA Lin X.;
RT "C-type lectin receptors Dectin-3 and Dectin-2 form a heterodimeric
RT pattern-recognition receptor for host defense against fungal infection.";
RL Immunity 39:324-334(2013).
RN [8]
RP X-RAY CRYSTALLOGRAPHY (2.29 ANGSTROMS) OF 61-215 IN COMPLEX WITH CALCIUM,
RP AND MUTAGENESIS OF GLU-173 AND ASP-175.
RX PubMed=24101491; DOI=10.1073/pnas.1312649110;
RA Furukawa A., Kamishikiryo J., Mori D., Toyonaga K., Okabe Y., Toji A.,
RA Kanda R., Miyake Y., Ose T., Yamasaki S., Maenaka K.;
RT "Structural analysis for glycolipid recognition by the C-type lectins
RT Mincle and MCL.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:17438-17443(2013).
CC -!- FUNCTION: Calcium-dependent lectin that acts as a pattern recognition
CC receptor (PRR) of the innate immune system: recognizes damage-
CC associated molecular patterns (DAMPs) of pathogen-associated molecular
CC patterns (PAMPs) of bacteria and fungi (PubMed:23602766,
CC PubMed:23911656). The PAMPs include alpha-mannans on C.albicans hypheas
CC and mycobacterial trehalose 6,6'-dimycolate (TDM) (PubMed:23602766,
CC PubMed:23911656). Interacts with signaling adapter Fc receptor gamma
CC chain/FCER1G, likely via CLEC4E, to form a functional complex in
CC myeloid cells (By similarity). Binding of mycobacterial TDM or
CC C.albicans alpha-mannans to this receptor complex leads to
CC phosphorylation of the immunoreceptor tyrosine-based activation motif
CC (ITAM) of FCER1G, triggering activation of SYK, CARD9 and NF-kappa-B,
CC consequently driving maturation of antigen-presenting cells and shaping
CC antigen-specific priming of T-cells toward effector T-helper 1 and T-
CC helper 17 cell subtypes (PubMed:23602766, PubMed:23911656). The
CC heterodimer formed with CLEC6A is active against fungal infection
CC (PubMed:23911656). Functions as an endocytic receptor
CC (PubMed:14971047). May be involved in antigen uptake at the site of
CC infection, either for clearance of the antigen, or for processing and
CC further presentation to T-cells (PubMed:14971047).
CC {ECO:0000250|UniProtKB:Q69FH1, ECO:0000269|PubMed:14971047,
CC ECO:0000269|PubMed:23602766, ECO:0000269|PubMed:23911656}.
CC -!- SUBUNIT: Heterodimer with CLEC4E; disulfide-linked (By similarity).
CC CLEC4E acts as a bridge for interaction between CLEC4D and FCER1G to
CC form a functional complex (By similarity). Heterodimer with CLEC6A;
CC this heterodimer forms a pattern recognition receptor (PRR) against
CC fungal infection (PubMed:23911656). {ECO:0000250|UniProtKB:Q69FH1,
CC ECO:0000269|PubMed:23911656}.
CC -!- INTERACTION:
CC Q8WXI8; P35609: ACTN2; NbExp=3; IntAct=EBI-12703404, EBI-77797;
CC Q8WXI8; Q86W74-2: ANKRD46; NbExp=3; IntAct=EBI-12703404, EBI-12109402;
CC Q8WXI8; Q8N5M9: JAGN1; NbExp=3; IntAct=EBI-12703404, EBI-10266796;
CC Q8WXI8; Q8N966: ZDHHC22; NbExp=3; IntAct=EBI-12703404, EBI-10268111;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:23911656};
CC Single-pass type II membrane protein {ECO:0000305}.
CC -!- TISSUE SPECIFICITY: Expressed weakly in peripheral blood leukocytes,
CC bone marrow and spleen. Expression is confined mostly in monocytes and
CC macrophage and seems to be up-regulated by IL-6, IL-10, TNF-alpha and
CC IFN-gamma. {ECO:0000269|PubMed:14971047}.
CC -!- INDUCTION: By autocrine inflammatory stimuli.
CC {ECO:0000269|PubMed:14971047}.
CC -!- WEB RESOURCE: Name=Functional Glycomics Gateway - Glycan Binding;
CC Note=MCL;
CC URL="http://www.functionalglycomics.org/glycomics/GBPServlet?&operationType=view&cbpId=cbp_hum_Ctlect_365";
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DR EMBL; AY297446; AAQ63173.1; -; mRNA.
DR EMBL; AY486482; AAS59161.1; -; mRNA.
DR EMBL; AY486483; AAS59162.1; -; mRNA.
DR EMBL; AF411850; AAL37713.1; -; mRNA.
DR EMBL; AY115592; AAM75389.1; -; mRNA.
DR EMBL; BC032313; AAH32313.1; -; mRNA.
DR CCDS; CCDS8593.1; -.
DR RefSeq; NP_525126.2; NM_080387.4.
DR RefSeq; XP_011518934.1; XM_011520632.2.
DR PDB; 2LS8; NMR; -; A=84-215.
DR PDB; 3WHD; X-ray; 2.29 A; A/C=61-215.
DR PDBsum; 2LS8; -.
DR PDBsum; 3WHD; -.
DR AlphaFoldDB; Q8WXI8; -.
DR BMRB; Q8WXI8; -.
DR SMR; Q8WXI8; -.
DR BioGRID; 130719; 261.
DR IntAct; Q8WXI8; 4.
DR STRING; 9606.ENSP00000299665; -.
DR UniLectin; Q8WXI8; -.
DR GlyGen; Q8WXI8; 3 sites.
DR iPTMnet; Q8WXI8; -.
DR PhosphoSitePlus; Q8WXI8; -.
DR BioMuta; CLEC4D; -.
DR DMDM; 73916933; -.
DR MassIVE; Q8WXI8; -.
DR PaxDb; Q8WXI8; -.
DR PeptideAtlas; Q8WXI8; -.
DR PRIDE; Q8WXI8; -.
DR ABCD; Q8WXI8; 1 sequenced antibody.
DR Antibodypedia; 1467; 290 antibodies from 30 providers.
DR DNASU; 338339; -.
DR Ensembl; ENST00000299665.3; ENSP00000299665.2; ENSG00000166527.8.
DR GeneID; 338339; -.
DR KEGG; hsa:338339; -.
DR MANE-Select; ENST00000299665.3; ENSP00000299665.2; NM_080387.5; NP_525126.2.
DR UCSC; uc001qun.4; human.
DR CTD; 338339; -.
DR DisGeNET; 338339; -.
DR GeneCards; CLEC4D; -.
DR HGNC; HGNC:14554; CLEC4D.
DR HPA; ENSG00000166527; Tissue enriched (bone).
DR MIM; 609964; gene.
DR neXtProt; NX_Q8WXI8; -.
DR OpenTargets; ENSG00000166527; -.
DR PharmGKB; PA134916109; -.
DR VEuPathDB; HostDB:ENSG00000166527; -.
DR eggNOG; KOG4297; Eukaryota.
DR GeneTree; ENSGT00940000162400; -.
DR HOGENOM; CLU_049894_7_5_1; -.
DR InParanoid; Q8WXI8; -.
DR OMA; WAWNDVP; -.
DR OrthoDB; 1269095at2759; -.
DR PhylomeDB; Q8WXI8; -.
DR TreeFam; TF333341; -.
DR PathwayCommons; Q8WXI8; -.
DR Reactome; R-HSA-5621480; Dectin-2 family.
DR Reactome; R-HSA-6798695; Neutrophil degranulation.
DR SignaLink; Q8WXI8; -.
DR BioGRID-ORCS; 338339; 11 hits in 1071 CRISPR screens.
DR GenomeRNAi; 338339; -.
DR Pharos; Q8WXI8; Tbio.
DR PRO; PR:Q8WXI8; -.
DR Proteomes; UP000005640; Chromosome 12.
DR RNAct; Q8WXI8; protein.
DR Bgee; ENSG00000166527; Expressed in bone marrow and 92 other tissues.
DR ExpressionAtlas; Q8WXI8; baseline and differential.
DR Genevisible; Q8WXI8; HS.
DR GO; GO:0009897; C:external side of plasma membrane; IBA:GO_Central.
DR GO; GO:0101003; C:ficolin-1-rich granule membrane; TAS:Reactome.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0035579; C:specific granule membrane; TAS:Reactome.
DR GO; GO:0070821; C:tertiary granule membrane; TAS:Reactome.
DR GO; GO:0030246; F:carbohydrate binding; IBA:GO_Central.
DR GO; GO:0034987; F:immunoglobulin receptor binding; IEA:Ensembl.
DR GO; GO:0005537; F:mannose binding; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0038187; F:pattern recognition receptor activity; IDA:UniProtKB.
DR GO; GO:0002250; P:adaptive immune response; IEA:UniProtKB-KW.
DR GO; GO:0061760; P:antifungal innate immune response; IDA:UniProtKB.
DR GO; GO:0042742; P:defense response to bacterium; IEA:Ensembl.
DR GO; GO:0038094; P:Fc-gamma receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0006955; P:immune response; IBA:GO_Central.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IEA:Ensembl.
DR GO; GO:0030887; P:positive regulation of myeloid dendritic cell activation; ISS:UniProtKB.
DR GO; GO:0002292; P:T cell differentiation involved in immune response; IEA:Ensembl.
DR CDD; cd03590; CLECT_DC-SIGN_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; IPR033989; CD209-like_CTLD.
DR InterPro; IPR016187; CTDL_fold.
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; Adaptive immunity; Calcium; Cell membrane; Disulfide bond;
KW Glycoprotein; Immunity; Innate immunity; Lectin; Membrane; Metal-binding;
KW Reference proteome; Signal-anchor; Transmembrane; Transmembrane helix.
FT CHAIN 1..215
FT /note="C-type lectin domain family 4 member D"
FT /id="PRO_0000046616"
FT TOPO_DOM 1..17
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 18..38
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 39..215
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT DOMAIN 91..208
FT /note="C-type lectin"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00040"
FT BINDING 173
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:24101491"
FT BINDING 175
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:24101491"
FT BINDING 195
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:24101491"
FT BINDING 196
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:24101491"
FT CARBOHYD 45
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 102
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 111
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 84..95
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00040"
FT DISULFID 112..207
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00040"
FT DISULFID 182..199
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00040"
FT VARIANT 32
FT /note="S -> G (in dbSNP:rs4304840)"
FT /evidence="ECO:0000269|Ref.3, ECO:0000269|Ref.4"
FT /id="VAR_021261"
FT MUTAGEN 173
FT /note="E->Q: No effect on already low affinity binding to
FT trehalose-6,6'-dimycolate."
FT /evidence="ECO:0000269|PubMed:24101491"
FT MUTAGEN 175
FT /note="D->N: No effect on already low affinity binding to
FT trehalose-6,6'-dimycolate."
FT /evidence="ECO:0000269|PubMed:24101491"
FT STRAND 63..67
FT /evidence="ECO:0007829|PDB:3WHD"
FT STRAND 81..85
FT /evidence="ECO:0007829|PDB:3WHD"
FT STRAND 88..91
FT /evidence="ECO:0007829|PDB:3WHD"
FT STRAND 94..103
FT /evidence="ECO:0007829|PDB:3WHD"
FT HELIX 105..113
FT /evidence="ECO:0007829|PDB:3WHD"
FT TURN 114..116
FT /evidence="ECO:0007829|PDB:3WHD"
FT STRAND 118..120
FT /evidence="ECO:0007829|PDB:2LS8"
FT HELIX 125..132
FT /evidence="ECO:0007829|PDB:3WHD"
FT STRAND 141..147
FT /evidence="ECO:0007829|PDB:3WHD"
FT STRAND 150..152
FT /evidence="ECO:0007829|PDB:3WHD"
FT STRAND 181..187
FT /evidence="ECO:0007829|PDB:3WHD"
FT STRAND 189..198
FT /evidence="ECO:0007829|PDB:3WHD"
FT STRAND 203..210
FT /evidence="ECO:0007829|PDB:3WHD"
FT STRAND 212..214
FT /evidence="ECO:0007829|PDB:3WHD"
SQ SEQUENCE 215 AA; 24704 MW; 938B68661AAC175B CRC64;
MGLEKPQSKL EGGMHPQLIP SVIAVVFILL LSVCFIASCL VTHHNFSRCK RGTGVHKLEH
HAKLKCIKEK SELKSAEGST WNCCPIDWRA FQSNCYFPLT DNKTWAESER NCSGMGAHLM
TISTEAEQNF IIQFLDRRLS YFLGLRDENA KGQWRWVDQT PFNPRRVFWH KNEPDNSQGE
NCVVLVYNQD KWAWNDVPCN FEASRICKIP GTTLN
