SIGL8_HUMAN
ID SIGL8_HUMAN Reviewed; 499 AA.
AC Q9NYZ4; Q7Z728;
DT 08-NOV-2002, integrated into UniProtKB/Swiss-Prot.
DT 08-NOV-2002, sequence version 2.
DT 03-AUG-2022, entry version 176.
DE RecName: Full=Sialic acid-binding Ig-like lectin 8;
DE Short=Siglec-8;
DE AltName: Full=Sialoadhesin family member 2;
DE Short=SAF-2;
DE Flags: Precursor;
GN Name=SIGLEC8; Synonyms=SAF2;
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 [GENOMIC DNA] (ISOFORM 1).
RX PubMed=11095983; DOI=10.1006/bbrc.2000.3866;
RA Foussias G., Yousef G.M., Diamandis E.P.;
RT "Molecular characterization of a siglec8 variant containing cytoplasmic
RT tyrosine-based motifs, and mapping of the siglec8 gene.";
RL Biochem. Biophys. Res. Commun. 278:775-781(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), TISSUE SPECIFICITY, AND FUNCTION.
RX PubMed=10856141; DOI=10.1067/mai.2000.107127;
RA Kikly K.K., Bochner B.S., Freeman S.D., Tan K.B., Gallagher K.T.,
RA D'Alessio K.J., Holmes S.D., Abrahamson J.A., Erickson-Miller C.L.,
RA Murdock P.R., Tachimoto H., Schleimer R.P., White J.R.;
RT "Identification of SAF-2, a novel siglec expressed on eosinophils, mast
RT cells, and basophils.";
RL J. Allergy Clin. Immunol. 105:1093-1100(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), TISSUE SPECIFICITY, AND FUNCTION.
RC TISSUE=Eosinophil;
RX PubMed=10625619; DOI=10.1074/jbc.275.2.861;
RA Floyd H., Ni J., Cornish A.L., Zeng Z., Liu D., Carter K.C., Steel J.,
RA Crocker P.R.;
RT "Siglec-8. A novel eosinophil-specific member of the immunoglobulin
RT superfamily.";
RL J. Biol. Chem. 275:861-866(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RA Floyd H., Zhang J.Q., Crocker P.R.;
RL Submitted (OCT-2000) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT PRO-170.
RC TISSUE=Spleen;
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] {ECO:0007744|PDB:2N7A, ECO:0007744|PDB:2N7B}
RP STRUCTURE BY NMR OF 17-155 IN COMPLEX WITH 6'-SULFO SIALYL-LEWIS X,
RP DISULFIDE BONDS, MUTAGENESIS OF ARG-72; TYR-74; GLN-75; ARG-125; LYS-132;
RP LYS-136 AND GLN-138, SITE, AND FUNCTION.
RX PubMed=27357658; DOI=10.1073/pnas.1602214113;
RA Propster J.M., Yang F., Rabbani S., Ernst B., Allain F.H., Schubert M.;
RT "Structural basis for sulfation-dependent self-glycan recognition by the
RT human immune-inhibitory receptor Siglec-8.";
RL Proc. Natl. Acad. Sci. U.S.A. 113:E4170-E4179(2016).
RN [7]
RP VARIANT LEU-282.
RX PubMed=21248752; DOI=10.1038/nature09639;
RA Varela I., Tarpey P., Raine K., Huang D., Ong C.K., Stephens P., Davies H.,
RA Jones D., Lin M.L., Teague J., Bignell G., Butler A., Cho J.,
RA Dalgliesh G.L., Galappaththige D., Greenman C., Hardy C., Jia M.,
RA Latimer C., Lau K.W., Marshall J., McLaren S., Menzies A., Mudie L.,
RA Stebbings L., Largaespada D.A., Wessels L.F.A., Richard S., Kahnoski R.J.,
RA Anema J., Tuveson D.A., Perez-Mancera P.A., Mustonen V., Fischer A.,
RA Adams D.J., Rust A., Chan-On W., Subimerb C., Dykema K., Furge K.,
RA Campbell P.J., Teh B.T., Stratton M.R., Futreal P.A.;
RT "Exome sequencing identifies frequent mutation of the SWI/SNF complex gene
RT PBRM1 in renal carcinoma.";
RL Nature 469:539-542(2011).
CC -!- FUNCTION: Putative adhesion molecule that mediates sialic-acid
CC dependent binding to red blood cells (PubMed:10856141,
CC PubMed:10625619). Preferentially binds to alpha-2,3-linked sialic acid.
CC Also binds to alpha-2,6-linked sialic acid. The sialic acid recognition
CC site may be masked by cis interactions with sialic acids on the same
CC cell surface (PubMed:10625619). Recognizes simultaneously epitopes
CC having a terminal N-acetylneuraminic acid (sialic acid) and an
CC underlying 6-O-sulfated galactose. Preferentially binds to Gal-6-
CC sulfated sialyl-Lewis X glycan epitopes (PubMed:27357658).
CC {ECO:0000269|PubMed:10625619, ECO:0000269|PubMed:10856141,
CC ECO:0000269|PubMed:27357658}.
CC -!- INTERACTION:
CC Q9NYZ4; P04155: TFF1; NbExp=3; IntAct=EBI-4314991, EBI-743871;
CC -!- SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=Long;
CC IsoId=Q9NYZ4-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9NYZ4-2; Sequence=VSP_002559;
CC Name=3;
CC IsoId=Q9NYZ4-3; Sequence=VSP_002560;
CC -!- TISSUE SPECIFICITY: Expressed specifically on red blood cells namely
CC basophil, mast cells and eosinophils. {ECO:0000269|PubMed:10625619,
CC ECO:0000269|PubMed:10856141}.
CC -!- DOMAIN: Contains 1 copy of a cytoplasmic motif that is referred to as
CC the immunoreceptor tyrosine-based inhibitor motif (ITIM). This motif is
CC involved in modulation of cellular responses. The phosphorylated ITIM
CC motif can bind the SH2 domain of several SH2-containing phosphatases.
CC -!- MISCELLANEOUS: [Isoform 3]: May be produced at very low levels due to a
CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA
CC decay. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the immunoglobulin superfamily. SIGLEC (sialic
CC acid binding Ig-like lectin) family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Functional Glycomics Gateway - Glycan Binding;
CC Note=Siglec-8;
CC URL="http://www.functionalglycomics.org/glycomics/GBPServlet?&operationType=view&cbpId=cbp_hum_Itlect_00146";
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DR EMBL; AF287892; AAG00573.1; -; Genomic_DNA.
DR EMBL; AF223403; AAF34702.1; -; mRNA.
DR EMBL; AF195092; AAF27622.1; -; mRNA.
DR EMBL; AF310234; AAK55140.1; -; mRNA.
DR EMBL; BC053319; AAH53319.1; -; mRNA.
DR CCDS; CCDS33086.1; -. [Q9NYZ4-1]
DR CCDS; CCDS86797.1; -. [Q9NYZ4-2]
DR RefSeq; NP_055257.2; NM_014442.2. [Q9NYZ4-1]
DR RefSeq; XP_011525037.1; XM_011526735.2.
DR PDB; 2N7A; NMR; -; A=17-155.
DR PDB; 2N7B; NMR; -; A=17-155.
DR PDBsum; 2N7A; -.
DR PDBsum; 2N7B; -.
DR AlphaFoldDB; Q9NYZ4; -.
DR SMR; Q9NYZ4; -.
DR BioGRID; 118057; 1.
DR IntAct; Q9NYZ4; 1.
DR STRING; 9606.ENSP00000321077; -.
DR ChEMBL; CHEMBL4630877; -.
DR UniLectin; Q9NYZ4; -.
DR GlyConnect; 570; 14 N-Linked glycans.
DR GlyGen; Q9NYZ4; 4 sites, 27 N-linked glycans (1 site).
DR iPTMnet; Q9NYZ4; -.
DR PhosphoSitePlus; Q9NYZ4; -.
DR BioMuta; SIGLEC8; -.
DR DMDM; 25009268; -.
DR jPOST; Q9NYZ4; -.
DR MassIVE; Q9NYZ4; -.
DR PaxDb; Q9NYZ4; -.
DR PeptideAtlas; Q9NYZ4; -.
DR PRIDE; Q9NYZ4; -.
DR ProteomicsDB; 83307; -. [Q9NYZ4-1]
DR ProteomicsDB; 83308; -. [Q9NYZ4-2]
DR ProteomicsDB; 83309; -. [Q9NYZ4-3]
DR Antibodypedia; 2297; 317 antibodies from 33 providers.
DR DNASU; 27181; -.
DR Ensembl; ENST00000321424.7; ENSP00000321077.2; ENSG00000105366.15. [Q9NYZ4-1]
DR Ensembl; ENST00000340550.5; ENSP00000339448.4; ENSG00000105366.15. [Q9NYZ4-2]
DR GeneID; 27181; -.
DR KEGG; hsa:27181; -.
DR MANE-Select; ENST00000321424.7; ENSP00000321077.2; NM_014442.3; NP_055257.2.
DR UCSC; uc002pwt.3; human. [Q9NYZ4-1]
DR CTD; 27181; -.
DR DisGeNET; 27181; -.
DR GeneCards; SIGLEC8; -.
DR HGNC; HGNC:10877; SIGLEC8.
DR HPA; ENSG00000105366; Tissue enhanced (brain, lymphoid tissue).
DR MIM; 605639; gene.
DR neXtProt; NX_Q9NYZ4; -.
DR OpenTargets; ENSG00000105366; -.
DR PharmGKB; PA35778; -.
DR VEuPathDB; HostDB:ENSG00000105366; -.
DR eggNOG; ENOG502S41V; Eukaryota.
DR GeneTree; ENSGT01040000240469; -.
DR HOGENOM; CLU_024444_6_1_1; -.
DR InParanoid; Q9NYZ4; -.
DR OMA; YPPWNLT; -.
DR OrthoDB; 324083at2759; -.
DR PhylomeDB; Q9NYZ4; -.
DR TreeFam; TF332441; -.
DR PathwayCommons; Q9NYZ4; -.
DR Reactome; R-HSA-198933; Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell.
DR SignaLink; Q9NYZ4; -.
DR BioGRID-ORCS; 27181; 20 hits in 1070 CRISPR screens.
DR GeneWiki; SIGLEC8; -.
DR GenomeRNAi; 27181; -.
DR Pharos; Q9NYZ4; Tbio.
DR PRO; PR:Q9NYZ4; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; Q9NYZ4; protein.
DR Bgee; ENSG00000105366; Expressed in C1 segment of cervical spinal cord and 110 other tissues.
DR ExpressionAtlas; Q9NYZ4; baseline and differential.
DR Genevisible; Q9NYZ4; HS.
DR GO; GO:0016021; C:integral component of membrane; TAS:ProtInc.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0030246; F:carbohydrate binding; TAS:ProtInc.
DR GO; GO:0033691; F:sialic acid binding; IBA:GO_Central.
DR GO; GO:0004888; F:transmembrane signaling receptor activity; TAS:ProtInc.
DR GO; GO:0007155; P:cell adhesion; IBA:GO_Central.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR Gene3D; 2.60.40.10; -; 3.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR036179; Ig-like_dom_sf.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR003599; Ig_sub.
DR InterPro; IPR003598; Ig_sub2.
DR InterPro; IPR013106; Ig_V-set.
DR Pfam; PF07686; V-set; 1.
DR SMART; SM00409; IG; 3.
DR SMART; SM00408; IGc2; 1.
DR SUPFAM; SSF48726; SSF48726; 3.
DR PROSITE; PS50835; IG_LIKE; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell adhesion; Disulfide bond;
KW Glycoprotein; Immunoglobulin domain; Lectin; Membrane; Reference proteome;
KW Repeat; Signal; Transmembrane; Transmembrane helix.
FT SIGNAL 1..16
FT /evidence="ECO:0000255"
FT CHAIN 17..499
FT /note="Sialic acid-binding Ig-like lectin 8"
FT /id="PRO_0000014948"
FT TOPO_DOM 17..363
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 364..384
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 385..499
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 40..123
FT /note="Ig-like V-type"
FT DOMAIN 157..240
FT /note="Ig-like C2-type 1"
FT DOMAIN 246..344
FT /note="Ig-like C2-type 2"
FT REGION 410..443
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 451..470
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 478..499
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 445..450
FT /note="ITIM motif"
FT MOTIF 468..473
FT /note="SLAM-like motif"
FT BINDING 23
FT /ligand="a carbohydrate"
FT /ligand_id="ChEBI:CHEBI:16646"
FT /evidence="ECO:0000269|PubMed:27357658,
FT ECO:0007744|PDB:2N7B"
FT BINDING 72..75
FT /ligand="a carbohydrate"
FT /ligand_id="ChEBI:CHEBI:16646"
FT /evidence="ECO:0000269|PubMed:27357658,
FT ECO:0007744|PDB:2N7B"
FT BINDING 125
FT /ligand="a carbohydrate"
FT /ligand_id="ChEBI:CHEBI:16646"
FT /evidence="ECO:0000269|PubMed:27357658,
FT ECO:0007744|PDB:2N7B"
FT BINDING 134..138
FT /ligand="a carbohydrate"
FT /ligand_id="ChEBI:CHEBI:16646"
FT /evidence="ECO:0000269|PubMed:27357658,
FT ECO:0007744|PDB:2N7B"
FT SITE 125
FT /note="Indispensable role in 6'-sulfo sialyl-Lewis X"
FT /evidence="ECO:0000269|PubMed:27357658"
FT CARBOHYD 172
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 249
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 267
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 42..181
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT DISULFID 47..107
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114,
FT ECO:0000269|PubMed:27357658, ECO:0007744|PDB:2N7A,
FT ECO:0007744|PDB:2N7B"
FT DISULFID 175..224
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT DISULFID 283..328
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT VAR_SEQ 152..245
FT /note="ALTHRPDILILGTLESGHSRNLTCSVPWACKQGTPPMISWIGASVSSPGPTT
FT ARSSVLTLTPKPQDHGTSLTCQVTLPGTGVTTTSTVRLDVSY -> D (in isoform
FT 2)"
FT /evidence="ECO:0000303|Ref.4"
FT /id="VSP_002559"
FT VAR_SEQ 416..499
FT /note="GPLTESWKDGNPLKKPPPAVAPSSGEEGELHYATLSFHKVKPQDPQGQEATD
FT SEYSEIKIHKRETAETQACLRNHNPSSKEVRG -> VSDVGFSTPSIQPGHL (in
FT isoform 3)"
FT /evidence="ECO:0000303|PubMed:10625619,
FT ECO:0000303|PubMed:10856141"
FT /id="VSP_002560"
FT VARIANT 170
FT /note="S -> P (in dbSNP:rs10409962)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_021487"
FT VARIANT 282
FT /note="V -> L (found in a renal cell carcinoma sample;
FT somatic mutation)"
FT /evidence="ECO:0000269|PubMed:21248752"
FT /id="VAR_064751"
FT VARIANT 388
FT /note="R -> G (in dbSNP:rs3829659)"
FT /id="VAR_049930"
FT MUTAGEN 72
FT /note="R->A: Strongly impaired binding to 6'-sulfo sialyl-
FT Lewis X."
FT /evidence="ECO:0000269|PubMed:27357658"
FT MUTAGEN 74
FT /note="Y->A: Modestly affected binding to 6'-sulfo sialyl-
FT Lewis X."
FT /evidence="ECO:0000269|PubMed:27357658"
FT MUTAGEN 75
FT /note="Q->A: Modestly affected binding to 6'-sulfo sialyl-
FT Lewis X."
FT /evidence="ECO:0000269|PubMed:27357658"
FT MUTAGEN 125
FT /note="R->A: Abolishes binding to 6'-sulfo sialyl-Lewis X."
FT /evidence="ECO:0000269|PubMed:27357658"
FT MUTAGEN 132
FT /note="K->A: Strongly impaired binding to 6'-sulfo sialyl-
FT Lewis X."
FT /evidence="ECO:0000269|PubMed:27357658"
FT MUTAGEN 136
FT /note="K->A: Strongly impaired binding to 6'-sulfo sialyl-
FT Lewis X."
FT /evidence="ECO:0000269|PubMed:27357658"
FT MUTAGEN 138
FT /note="Q->A: Minor effects on binding to 6'-sulfo sialyl-
FT Lewis X."
FT /evidence="ECO:0000269|PubMed:27357658"
FT HELIX 18..20
FT /evidence="ECO:0007829|PDB:2N7A"
FT TURN 23..26
FT /evidence="ECO:0007829|PDB:2N7A"
FT STRAND 28..31
FT /evidence="ECO:0007829|PDB:2N7A"
FT STRAND 33..38
FT /evidence="ECO:0007829|PDB:2N7A"
FT STRAND 43..45
FT /evidence="ECO:0007829|PDB:2N7A"
FT STRAND 47..50
FT /evidence="ECO:0007829|PDB:2N7A"
FT STRAND 62..68
FT /evidence="ECO:0007829|PDB:2N7A"
FT TURN 73..75
FT /evidence="ECO:0007829|PDB:2N7A"
FT STRAND 79..82
FT /evidence="ECO:0007829|PDB:2N7A"
FT TURN 90..95
FT /evidence="ECO:0007829|PDB:2N7A"
FT STRAND 96..98
FT /evidence="ECO:0007829|PDB:2N7A"
FT HELIX 102..104
FT /evidence="ECO:0007829|PDB:2N7A"
FT STRAND 109..113
FT /evidence="ECO:0007829|PDB:2N7A"
FT HELIX 116..118
FT /evidence="ECO:0007829|PDB:2N7A"
FT STRAND 120..128
FT /evidence="ECO:0007829|PDB:2N7A"
FT STRAND 131..134
FT /evidence="ECO:0007829|PDB:2N7A"
FT STRAND 146..151
FT /evidence="ECO:0007829|PDB:2N7A"
FT STRAND 153..155
FT /evidence="ECO:0007829|PDB:2N7A"
SQ SEQUENCE 499 AA; 54042 MW; 086EFF989B74123C CRC64;
MLLLLLLLPL LWGTKGMEGD RQYGDGYLLQ VQELVTVQEG LCVHVPCSFS YPQDGWTDSD
PVHGYWFRAG DRPYQDAPVA TNNPDREVQA ETQGRFQLLG DIWSNDCSLS IRDARKRDKG
SYFFRLERGS MKWSYKSQLN YKTKQLSVFV TALTHRPDIL ILGTLESGHS RNLTCSVPWA
CKQGTPPMIS WIGASVSSPG PTTARSSVLT LTPKPQDHGT SLTCQVTLPG TGVTTTSTVR
LDVSYPPWNL TMTVFQGDAT ASTALGNGSS LSVLEGQSLR LVCAVNSNPP ARLSWTRGSL
TLCPSRSSNP GLLELPRVHV RDEGEFTCRA QNAQGSQHIS LSLSLQNEGT GTSRPVSQVT
LAAVGGAGAT ALAFLSFCII FIIVRSCRKK SARPAAGVGD TGMEDAKAIR GSASQGPLTE
SWKDGNPLKK PPPAVAPSSG EEGELHYATL SFHKVKPQDP QGQEATDSEY SEIKIHKRET
AETQACLRNH NPSSKEVRG
