TSG6_HUMAN
ID TSG6_HUMAN Reviewed; 277 AA.
AC P98066; Q53TI7; Q8WWI9;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
DT 21-JUN-2005, sequence version 2.
DT 03-AUG-2022, entry version 190.
DE RecName: Full=Tumor necrosis factor-inducible gene 6 protein;
DE EC=3.1.1.- {ECO:0000305|PubMed:20463016};
DE AltName: Full=Hyaluronate-binding protein;
DE AltName: Full=TNF-stimulated gene 6 protein;
DE Short=TSG-6 {ECO:0000303|PubMed:1730767};
DE AltName: Full=Tumor necrosis factor alpha-induced protein 6;
DE Short=TNF alpha-induced protein 6;
DE Flags: Precursor;
GN Name=TNFAIP6; Synonyms=TSG6;
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], VARIANT ARG-144, INDUCTION BY TNF, SUBCELLULAR
RP LOCATION, AND PTM.
RC TISSUE=Fibroblast;
RX PubMed=1730767; DOI=10.1083/jcb.116.2.545;
RA Lee T.H., Wisniewski H.-G., Vilcek J.;
RT "A novel secretory tumor necrosis factor-inducible protein (TSG-6) is a
RT member of the family of hyaluronate binding proteins, closely related to
RT the adhesion receptor CD44.";
RL J. Cell Biol. 116:545-557(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=11854277; DOI=10.1074/jbc.m110765200;
RA Nentwich H.A., Mustafa Z., Rugg M.S., Marsden B.D., Cordell M.R.,
RA Mahoney D.J., Jenkins S.C., Dowling B., Fries E., Milner C.M., Loughlin J.,
RA Day A.J.;
RT "A novel allelic variant of the human TSG-6 gene encoding an amino acid
RT difference in the CUB module. Chromosomal localization, frequency analysis,
RT modeling, and expression.";
RL J. Biol. Chem. 277:15354-15362(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ARG-144.
RC TISSUE=Lung, and 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]
RP PROTEIN SEQUENCE OF 18-27, TISSUE SPECIFICITY, AND INTERACTION WITH
RP INTER-ALPHA-INHIBITOR.
RX PubMed=7516184; DOI=10.1021/bi00189a049;
RA Wisniewski H.-G., Burgess W.H., Oppenheim J.D., Vilcek J.;
RT "TSG-6, an arthritis-associated hyaluronan binding protein, forms a stable
RT complex with the serum protein inter-alpha-inhibitor.";
RL Biochemistry 33:7423-7429(1994).
RN [7]
RP FUNCTION, DOMAIN, AND MUTAGENESIS OF HIS-39; GLU-41; TYR-47; LYS-48;
RP HIS-64; PHE-105 AND TYR-113.
RX PubMed=15060082; DOI=10.1074/jbc.m313319200;
RA Lesley J., Gal I., Mahoney D.J., Cordell M.R., Rugg M.S., Hyman R.,
RA Day A.J., Mikecz K.;
RT "TSG-6 modulates the interaction between hyaluronan and cell surface
RT CD44.";
RL J. Biol. Chem. 279:25745-25754(2004).
RN [8]
RP FUNCTION, INTERACTION WITH BIKUNIN, DOMAIN, AND MUTAGENESIS OF LYS-46;
RP TYR-47; LYS-55; LYS-69; LYS-76; LYS-89; TYR-94 AND TYR-113.
RX PubMed=15917224; DOI=10.1074/jbc.m502068200;
RA Mahoney D.J., Mulloy B., Forster M.J., Blundell C.D., Fries E.,
RA Milner C.M., Day A.J.;
RT "Characterization of the interaction between tumor necrosis factor-
RT stimulated gene-6 and heparin: implications for the inhibition of plasmin
RT in extracellular matrix microenvironments.";
RL J. Biol. Chem. 280:27044-27055(2005).
RN [9]
RP FUNCTION, TISSUE SPECIFICITY, INDUCTION, AND INTERACTION WITH BMP2.
RX PubMed=16771708; DOI=10.1042/bj20060027;
RA Tsukahara S., Ikeda R., Goto S., Yoshida K., Mitsumori R., Sakamoto Y.,
RA Tajima A., Yokoyama T., Toh S., Furukawa K., Inoue I.;
RT "Tumour necrosis factor alpha-stimulated gene-6 inhibits osteoblastic
RT differentiation of human mesenchymal stem cells induced by osteogenic
RT differentiation medium and BMP-2.";
RL Biochem. J. 398:595-603(2006).
RN [10]
RP FUNCTION, TISSUE SPECIFICITY, AND INDUCTION BY TNF.
RX PubMed=16873769; DOI=10.1165/rcmb.2006-0018oc;
RA Forteza R., Casalino-Matsuda S.M., Monzon M.E., Fries E., Rugg M.S.,
RA Milner C.M., Day A.J.;
RT "TSG-6 potentiates the antitissue kallikrein activity of inter-alpha-
RT inhibitor through bikunin release.";
RL Am. J. Respir. Cell Mol. Biol. 36:20-31(2007).
RN [11]
RP FUNCTION, AND INTERACTION WITH TNFSF11.
RX PubMed=18586671; DOI=10.1074/jbc.m802138200;
RA Mahoney D.J., Mikecz K., Ali T., Mabilleau G., Benayahu D., Plaas A.,
RA Milner C.M., Day A.J., Sabokbar A.;
RT "TSG-6 regulates bone remodeling through inhibition of osteoblastogenesis
RT and osteoclast activation.";
RL J. Biol. Chem. 283:25952-25962(2008).
RN [12]
RP FUNCTION, DOMAIN, AND INTERACTION WITH FN1.
RX PubMed=18042364; DOI=10.1016/j.matbio.2007.10.003;
RA Kuznetsova S.A., Mahoney D.J., Martin-Manso G., Ali T., Nentwich H.A.,
RA Sipes J.M., Zeng B., Vogel T., Day A.J., Roberts D.D.;
RT "TSG-6 binds via its CUB_C domain to the cell-binding domain of fibronectin
RT and increases fibronectin matrix assembly.";
RL Matrix Biol. 27:201-210(2008).
RN [13]
RP FUNCTION, AND SUBUNIT.
RX PubMed=20463016; DOI=10.1074/jbc.m109.041046;
RA Sanggaard K.W., Scavenius C., Rasmussen A.J., Wisniewski H.G.,
RA Thoegersen I.B., Enghild J.J.;
RT "The TSG-6/HC2-mediated transfer is a dynamic process shuffling heavy
RT chains between glycosaminoglycans.";
RL J. Biol. Chem. 285:21988-21993(2010).
RN [14]
RP FUNCTION, INTERACTION WITH CXCL8, AND MUTAGENESIS OF LYS-55; LYS-69 AND
RP LYS-76.
RX PubMed=24501198; DOI=10.4049/jimmunol.1300194;
RA Dyer D.P., Thomson J.M., Hermant A., Jowitt T.A., Handel T.M.,
RA Proudfoot A.E., Day A.J., Milner C.M.;
RT "TSG-6 inhibits neutrophil migration via direct interaction with the
RT chemokine CXCL8.";
RL J. Immunol. 192:2177-2185(2014).
RN [15]
RP FUNCTION.
RX PubMed=26823460; DOI=10.1074/jbc.m115.708305;
RA Lawrance W., Banerji S., Day A.J., Bhattacharjee S., Jackson D.G.;
RT "Binding of Hyaluronan to the Native Lymphatic Vessel Endothelial Receptor
RT LYVE-1 Is Critically Dependent on Receptor Clustering and Hyaluronan
RT Organization.";
RL J. Biol. Chem. 291:8014-8030(2016).
RN [16]
RP FUNCTION, INTERACTION WITH PF4; CXCL11; CXCL12; CCL2; CCL7; CCL19; CCL21
RP AND CCL27, AND DOMAIN.
RX PubMed=27044744; DOI=10.1074/jbc.m116.720953;
RA Dyer D.P., Salanga C.L., Johns S.C., Valdambrini E., Fuster M.M.,
RA Milner C.M., Day A.J., Handel T.M.;
RT "The Anti-inflammatory Protein TSG-6 Regulates Chemokine Function by
RT Inhibiting Chemokine/Glycosaminoglycan Interactions.";
RL J. Biol. Chem. 291:12627-12640(2016).
RN [17]
RP STRUCTURE BY NMR OF 36-133.
RX PubMed=8797823; DOI=10.1016/s0092-8674(00)80151-8;
RA Kohda D., Morton C.J., Parkar A.A., Hatanaka H., Inagaki F.M.,
RA Campbell I.D., Day A.J.;
RT "Solution structure of the link module: a hyaluronan-binding domain
RT involved in extracellular matrix stability and cell migration.";
RL Cell 86:767-775(1996).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 129-277 IN COMPLEX WITH CALCIUM,
RP FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, DOMAIN, INTERACTION WITH ITIH1,
RP AND MUTAGENESIS OF TYR-47; TYR-94; TYR-113 AND GLU-183.
RX PubMed=26468290; DOI=10.1074/jbc.m115.669838;
RA Briggs D.C., Birchenough H.L., Ali T., Rugg M.S., Waltho J.P., Ievoli E.,
RA Jowitt T.A., Enghild J.J., Richter R.P., Salustri A., Milner C.M.,
RA Day A.J.;
RT "Metal Ion-dependent Heavy Chain Transfer Activity of TSG-6 Mediates
RT Assembly of the Cumulus-Oocyte Matrix.";
RL J. Biol. Chem. 290:28708-28723(2015).
CC -!- FUNCTION: Major regulator of extracellular matrix organization during
CC tissue remodeling (PubMed:18042364, PubMed:26823460, PubMed:15917224).
CC Catalyzes the transfer of a heavy chain (HC) from inter-alpha-inhibitor
CC (I-alpha-I) complex to hyaluronan. Cleaves the ester bond between the
CC C-terminus of the HC and GalNAc residue of the chondroitin sulfate
CC chain in I-alpha-I complex followed by transesterification of the HC to
CC hyaluronan. In the process, potentiates the antiprotease function of I-
CC alpha-I complex through release of free bikunin (PubMed:20463016,
CC PubMed:15917224, PubMed:16873769). Acts as a catalyst in the formation
CC of hyaluronan-HC oligomers and hyaluronan-rich matrix surrounding the
CC cumulus cell-oocyte complex, a necessary step for oocyte fertilization
CC (PubMed:26468290). Assembles hyaluronan in pericellular matrices that
CC serve as platforms for receptor clustering and signaling. Enables
CC binding of hyaluronan deposited on the surface of macrophages to LYVE1
CC on lymphatic endothelium and facilitates macrophage extravasation.
CC Alters hyaluronan binding to functionally latent CD44 on vascular
CC endothelium, switching CD44 into an active state that supports
CC leukocyte rolling (PubMed:26823460, PubMed:15060082). Modulates the
CC interaction of chemokines with extracellular matrix components and
CC proteoglycans on endothelial cell surface, likely preventing chemokine
CC gradient formation (PubMed:27044744). In a negative feedback mechanism,
CC may limit excessive neutrophil recruitment at inflammatory sites by
CC antagonizing the association of CXCL8 with glycosaminoglycans on
CC vascular endothelium (PubMed:24501198). Has a role in osteogenesis and
CC bone remodeling. Inhibits BMP2-dependent differentiation of mesenchymal
CC stem cell to osteoblasts (PubMed:18586671, PubMed:16771708). Protects
CC against bone erosion during inflammation by inhibiting TNFSF11/RANKL-
CC dependent osteoclast activation (PubMed:18586671).
CC {ECO:0000269|PubMed:15060082, ECO:0000269|PubMed:15917224,
CC ECO:0000269|PubMed:16771708, ECO:0000269|PubMed:16873769,
CC ECO:0000269|PubMed:18042364, ECO:0000269|PubMed:18586671,
CC ECO:0000269|PubMed:20463016, ECO:0000269|PubMed:24501198,
CC ECO:0000269|PubMed:26468290, ECO:0000269|PubMed:26823460,
CC ECO:0000269|PubMed:27044744}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC pH dependence:
CC Optimally active at pH 6.5-8. {ECO:0000269|PubMed:26468290};
CC -!- SUBUNIT: Interacts (via Link domain) with inter-alpha-inhibitor (I-
CC alpha-I) component bikunin (PubMed:15917224). Interacts with ITIH2/HC2;
CC this interaction is required for transesterification of the HC to
CC hyaluronan (PubMed:20463016). Interacts (via Link and CUB domains) with
CC ITIH1 (PubMed:26468290). Chondroitin sulfate may be required for the
CC stability of the complex (PubMed:7516184). Interacts (via Link domain)
CC with various C-X-C and C-C chemokines including PF4, CXCL8, CXCL11,
CC CXCL12, CCL2, CCL7, CCL19, CCL21, and CCL27; this interaction
CC interferes with chemokine binding to glycosaminoglycans
CC (PubMed:24501198, PubMed:27044744). Interacts (primarily via Link
CC domain) with BMP2; this interaction is inhibited by hyaluronan
CC (PubMed:16771708). Interacts (via both Link and CUB domains) with
CC TNFSF11 (PubMed:18586671). Interacts (via CUB domain) with FN1 (via
CC type III repeats 9-14); this interaction enhances fibronectin fibril
CC assembly. TNFAIP6 may act as a bridging molecule between FN1 and THBS1
CC (PubMed:18042364). {ECO:0000269|PubMed:15917224,
CC ECO:0000269|PubMed:16771708, ECO:0000269|PubMed:18042364,
CC ECO:0000269|PubMed:18586671, ECO:0000269|PubMed:20463016,
CC ECO:0000269|PubMed:24501198, ECO:0000269|PubMed:26468290,
CC ECO:0000269|PubMed:27044744, ECO:0000269|PubMed:7516184}.
CC -!- INTERACTION:
CC P98066; PRO_0000033825 [P12643]: BMP2; NbExp=3; IntAct=EBI-11700693, EBI-9697918;
CC P98066; PRO_0000005214 [Q99731]: CCL19; NbExp=2; IntAct=EBI-11700693, EBI-11711510;
CC P98066; PRO_0000005146 [P13500]: CCL2; NbExp=2; IntAct=EBI-11700693, EBI-11711396;
CC P98066; PRO_0000005183 [P80098]: CCL7; NbExp=2; IntAct=EBI-11700693, EBI-11711410;
CC P98066; PRO_0000005106 [O14625]: CXCL11; NbExp=2; IntAct=EBI-11700693, EBI-11711364;
CC P98066; P10145: CXCL8; NbExp=15; IntAct=EBI-11700693, EBI-3917999;
CC P98066; P02751: FN1; NbExp=8; IntAct=EBI-11700693, EBI-1220319;
CC P98066; PRO_0000033913 [P43026]: GDF5; NbExp=3; IntAct=EBI-11700693, EBI-11710512;
CC P98066; PRO_0000042253 [Q6KF10]: GDF6; NbExp=3; IntAct=EBI-11700693, EBI-11710019;
CC P98066; P26022: PTX3; NbExp=8; IntAct=EBI-11700693, EBI-11574553;
CC P98066; O14788: TNFSF11; NbExp=4; IntAct=EBI-11700693, EBI-7404021;
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:1730767}.
CC -!- TISSUE SPECIFICITY: Expressed in airway epithelium and submucosal gland
CC (at protein level). Colocalizes with bikunin at the ciliary border.
CC Present in bronchoalveolar lavage fluid (at protein level)
CC (PubMed:16873769). Expressed in mesenchymal stem cells
CC (PubMed:16771708). Found in the synovial fluid of patients with
CC rheumatoid arthritis. {ECO:0000269|PubMed:16771708,
CC ECO:0000269|PubMed:16873769, ECO:0000269|PubMed:7516184}.
CC -!- INDUCTION: Up-regulated in peripheral blood mononuclear cells, high
CC endothelial venules, airway epithelium and submucosal gland in response
CC to inflammatory cytokine TNF (PubMed:1730767, PubMed:16873769). Down-
CC regulated upon differentiation of mesenchymal stem cells to osteoblasts
CC (PubMed:16771708). {ECO:0000269|PubMed:16771708,
CC ECO:0000269|PubMed:16873769, ECO:0000269|PubMed:1730767}.
CC -!- DOMAIN: The Link domain interacts with various extracellular matrix
CC components, including heparin, heparan sulfates, hyaluronan and I-
CC alpha-I complex (PubMed:15917224, PubMed:15060082). It is required for
CC binding to various chemokines (PubMed:27044744).
CC {ECO:0000269|PubMed:15060082, ECO:0000269|PubMed:15917224,
CC ECO:0000269|PubMed:27044744}.
CC -!- DOMAIN: The CUB domain is necessary for calcium ion binding and
CC transesterification reaction (PubMed:26468290). It is required for
CC binding to FN1 (PubMed:18042364). {ECO:0000269|PubMed:18042364,
CC ECO:0000269|PubMed:26468290}.
CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:1730767}.
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DR EMBL; M31165; AAB00792.1; -; mRNA.
DR EMBL; AJ421518; CAD13434.1; -; mRNA.
DR EMBL; AJ419936; CAD12353.1; -; mRNA.
DR EMBL; AC009311; AAY15067.1; -; Genomic_DNA.
DR EMBL; CH471058; EAX11511.1; -; Genomic_DNA.
DR EMBL; BC030205; AAH30205.1; -; mRNA.
DR CCDS; CCDS2193.1; -.
DR PIR; A41735; A41735.
DR RefSeq; NP_009046.2; NM_007115.3.
DR PDB; 1O7B; NMR; -; T=36-133.
DR PDB; 1O7C; NMR; -; T=36-133.
DR PDB; 2N40; NMR; -; A=36-133.
DR PDB; 2PF5; X-ray; 1.90 A; A/B/C/D/E=36-133.
DR PDB; 2WNO; X-ray; 2.30 A; A=129-277.
DR PDBsum; 1O7B; -.
DR PDBsum; 1O7C; -.
DR PDBsum; 2N40; -.
DR PDBsum; 2PF5; -.
DR PDBsum; 2WNO; -.
DR AlphaFoldDB; P98066; -.
DR BMRB; P98066; -.
DR SMR; P98066; -.
DR BioGRID; 112984; 26.
DR IntAct; P98066; 25.
DR STRING; 9606.ENSP00000243347; -.
DR DrugBank; DB00945; Acetylsalicylic acid.
DR DrugBank; DB00843; Donepezil.
DR DrugBank; DB08818; Hyaluronic acid.
DR GlyGen; P98066; 2 sites.
DR iPTMnet; P98066; -.
DR PhosphoSitePlus; P98066; -.
DR BioMuta; TNFAIP6; -.
DR DMDM; 68067717; -.
DR MassIVE; P98066; -.
DR PaxDb; P98066; -.
DR PeptideAtlas; P98066; -.
DR PRIDE; P98066; -.
DR ProteomicsDB; 57783; -.
DR Antibodypedia; 33651; 196 antibodies from 32 providers.
DR DNASU; 7130; -.
DR Ensembl; ENST00000243347.5; ENSP00000243347.3; ENSG00000123610.5.
DR GeneID; 7130; -.
DR KEGG; hsa:7130; -.
DR MANE-Select; ENST00000243347.5; ENSP00000243347.3; NM_007115.4; NP_009046.2.
DR UCSC; uc002txk.3; human.
DR CTD; 7130; -.
DR DisGeNET; 7130; -.
DR GeneCards; TNFAIP6; -.
DR HGNC; HGNC:11898; TNFAIP6.
DR HPA; ENSG00000123610; Tissue enriched (urinary).
DR MIM; 600410; gene.
DR neXtProt; NX_P98066; -.
DR OpenTargets; ENSG00000123610; -.
DR PharmGKB; PA36595; -.
DR VEuPathDB; HostDB:ENSG00000123610; -.
DR eggNOG; KOG1218; Eukaryota.
DR eggNOG; KOG3714; Eukaryota.
DR GeneTree; ENSGT00940000157201; -.
DR HOGENOM; CLU_092089_0_0_1; -.
DR InParanoid; P98066; -.
DR OMA; DDTACMA; -.
DR OrthoDB; 934805at2759; -.
DR PhylomeDB; P98066; -.
DR TreeFam; TF334173; -.
DR PathwayCommons; P98066; -.
DR Reactome; R-HSA-6798695; Neutrophil degranulation.
DR SignaLink; P98066; -.
DR SIGNOR; P98066; -.
DR BioGRID-ORCS; 7130; 13 hits in 1077 CRISPR screens.
DR ChiTaRS; TNFAIP6; human.
DR EvolutionaryTrace; P98066; -.
DR GeneWiki; TSG-6; -.
DR GenomeRNAi; 7130; -.
DR Pharos; P98066; Tbio.
DR PRO; PR:P98066; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; P98066; protein.
DR Bgee; ENSG00000123610; Expressed in cartilage tissue and 162 other tissues.
DR Genevisible; P98066; HS.
DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:1904813; C:ficolin-1-rich granule lumen; TAS:Reactome.
DR GO; GO:1904724; C:tertiary granule lumen; TAS:Reactome.
DR GO; GO:0005509; F:calcium ion binding; IDA:UniProtKB.
DR GO; GO:0052689; F:carboxylic ester hydrolase activity; IDA:UniProtKB.
DR GO; GO:0001968; F:fibronectin binding; IDA:UniProtKB.
DR GO; GO:0005540; F:hyaluronic acid binding; IDA:UniProtKB.
DR GO; GO:0007155; P:cell adhesion; IEA:UniProtKB-KW.
DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc.
DR GO; GO:1905590; P:fibronectin fibril organization; IDA:UniProtKB.
DR GO; GO:0030212; P:hyaluronan metabolic process; IDA:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; TAS:ProtInc.
DR GO; GO:0030514; P:negative regulation of BMP signaling pathway; IDA:UniProtKB.
DR GO; GO:0050728; P:negative regulation of inflammatory response; IDA:CACAO.
DR GO; GO:0090024; P:negative regulation of neutrophil chemotaxis; IDA:UniProtKB.
DR GO; GO:0045668; P:negative regulation of osteoblast differentiation; IDA:UniProtKB.
DR GO; GO:0045671; P:negative regulation of osteoclast differentiation; IDA:UniProtKB.
DR GO; GO:0001550; P:ovarian cumulus expansion; ISS:UniProtKB.
DR GO; GO:0030728; P:ovulation; IEA:Ensembl.
DR GO; GO:0030335; P:positive regulation of cell migration; IEA:Ensembl.
DR GO; GO:1903911; P:positive regulation of receptor clustering; IDA:UniProtKB.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR CDD; cd00041; CUB; 1.
DR Gene3D; 2.60.120.290; -; 1.
DR Gene3D; 3.10.100.10; -; 1.
DR InterPro; IPR016186; C-type_lectin-like/link_sf.
DR InterPro; IPR016187; CTDL_fold.
DR InterPro; IPR000859; CUB_dom.
DR InterPro; IPR000538; Link_dom.
DR InterPro; IPR035914; Sperma_CUB_dom_sf.
DR Pfam; PF00431; CUB; 1.
DR Pfam; PF00193; Xlink; 1.
DR PRINTS; PR01265; LINKMODULE.
DR SMART; SM00042; CUB; 1.
DR SMART; SM00445; LINK; 1.
DR SUPFAM; SSF49854; SSF49854; 1.
DR SUPFAM; SSF56436; SSF56436; 1.
DR PROSITE; PS01180; CUB; 1.
DR PROSITE; PS01241; LINK_1; 1.
DR PROSITE; PS50963; LINK_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Calcium; Cell adhesion; Direct protein sequencing;
KW Disulfide bond; Glycoprotein; Hydrolase; Metal-binding; Reference proteome;
KW Secreted; Signal.
FT SIGNAL 1..17
FT /evidence="ECO:0000269|PubMed:7516184"
FT CHAIN 18..277
FT /note="Tumor necrosis factor-inducible gene 6 protein"
FT /id="PRO_0000026692"
FT DOMAIN 36..129
FT /note="Link"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00323"
FT DOMAIN 135..247
FT /note="CUB"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00059"
FT BINDING 183
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:26468290,
FT ECO:0007744|PDB:2WNO"
FT BINDING 191
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:26468290,
FT ECO:0007744|PDB:2WNO"
FT BINDING 232
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:26468290,
FT ECO:0007744|PDB:2WNO"
FT BINDING 234
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:26468290,
FT ECO:0007744|PDB:2WNO"
FT BINDING 235
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:26468290,
FT ECO:0007744|PDB:2WNO"
FT CARBOHYD 118
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 258
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 58..127
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00323"
FT DISULFID 82..103
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00323"
FT DISULFID 135..161
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00059"
FT DISULFID 188..210
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00059"
FT VARIANT 144
FT /note="Q -> R (in dbSNP:rs1046668)"
FT /evidence="ECO:0000269|PubMed:15489334,
FT ECO:0000269|PubMed:1730767"
FT /id="VAR_013005"
FT MUTAGEN 39
FT /note="H->K: Decreases binding of hyaluronan to CD44.
FT Decreases hyaluronan-dependent lymphocyte rolling."
FT /evidence="ECO:0000269|PubMed:15060082"
FT MUTAGEN 41
FT /note="E->K: Has no significant effect on hyaluronan
FT binding to CD44 or hyaluronan-dependent lymphocyte
FT rolling."
FT /evidence="ECO:0000269|PubMed:15060082"
FT MUTAGEN 46
FT /note="K->Q: Abolishes binding to bikunin."
FT /evidence="ECO:0000269|PubMed:15917224"
FT MUTAGEN 47
FT /note="Y->F: Abolishes binding to bikunin. Impairs binding
FT to hyaluronan. Retains the ability to bind heavy chains but
FT cannot transfer them onto hyaluronan. Impairs binding of
FT hyaluronan to CD44. Decreases hyaluronan-dependent
FT lymphocyte rolling."
FT /evidence="ECO:0000269|PubMed:15060082,
FT ECO:0000269|PubMed:15917224, ECO:0000269|PubMed:26468290"
FT MUTAGEN 48
FT /note="K->E: Decreases binding of hyaluronan to CD44.
FT Decreases hyaluronan-dependent lymphocyte rolling."
FT /evidence="ECO:0000269|PubMed:15060082"
FT MUTAGEN 55
FT /note="K->A: Decreases binding to heparin. Has normal
FT binding to bikunin. Impairs binding to heparin; when
FT associated with A-69 and A-76. Has no effect on CXCL8-
FT induced neutrophil transmigration; when associated with A-
FT 69 and A-76."
FT /evidence="ECO:0000269|PubMed:15917224,
FT ECO:0000269|PubMed:24501198"
FT MUTAGEN 64
FT /note="H->K: Increases binding of hyaluronan to CD44. Has
FT no significant effect on hyaluronan-dependent lymphocyte
FT rolling."
FT /evidence="ECO:0000269|PubMed:15060082"
FT MUTAGEN 69
FT /note="K->A: Decreases binding to heparin. Has normal
FT binding to bikunin. Impairs binding to heparin; when
FT associated with A-55 and A-76. Has no effect on CXCL8-
FT induced neutrophil transmigration; when associated with A-
FT 55 and A-76."
FT /evidence="ECO:0000269|PubMed:15917224,
FT ECO:0000269|PubMed:24501198"
FT MUTAGEN 76
FT /note="K->A: Decreases binding to heparin. Has normal
FT binding to bikunin. Impairs binding to heparin and
FT decreases the potentiation effect toward bikunin
FT antiprotease activity; when associated with A-55 and A-69.
FT Has no effect on CXCL8-induced neutrophil transmigration;
FT when associated with A-55 and A-69."
FT /evidence="ECO:0000269|PubMed:15917224,
FT ECO:0000269|PubMed:24501198"
FT MUTAGEN 89
FT /note="K->A: Decreases binding to heparin. Has normal
FT binding to bikunin."
FT /evidence="ECO:0000269|PubMed:15917224"
FT MUTAGEN 94
FT /note="Y->F: Abolishes binding to bikunin. Has no effect on
FT transesterification reaction."
FT /evidence="ECO:0000269|PubMed:15917224,
FT ECO:0000269|PubMed:26468290"
FT MUTAGEN 105
FT /note="F->V: Impairs binding of hyaluronan to CD44.
FT Decreases hyaluronan-dependent lymphocyte rolling."
FT /evidence="ECO:0000269|PubMed:15060082"
FT MUTAGEN 113
FT /note="Y->F: Abolishes binding to bikunin. Impairs binding
FT of hyaluronan to CD44. Decreases hyaluronan-dependent
FT lymphocyte rolling. Has no effect on transesterification
FT reaction."
FT /evidence="ECO:0000269|PubMed:15060082,
FT ECO:0000269|PubMed:15917224, ECO:0000269|PubMed:26468290"
FT MUTAGEN 183
FT /note="E->S: Reduces the binding affinity to calcium ions.
FT Abolishes the interaction with heavy chain ITIH1."
FT /evidence="ECO:0000269|PubMed:26468290"
FT STRAND 37..40
FT /evidence="ECO:0007829|PDB:2PF5"
FT STRAND 42..44
FT /evidence="ECO:0007829|PDB:1O7B"
FT STRAND 45..47
FT /evidence="ECO:0007829|PDB:2PF5"
FT HELIX 51..60
FT /evidence="ECO:0007829|PDB:2PF5"
FT HELIX 68..76
FT /evidence="ECO:0007829|PDB:2PF5"
FT STRAND 85..87
FT /evidence="ECO:0007829|PDB:1O7B"
FT HELIX 88..90
FT /evidence="ECO:0007829|PDB:2PF5"
FT STRAND 91..97
FT /evidence="ECO:0007829|PDB:2PF5"
FT TURN 101..103
FT /evidence="ECO:0007829|PDB:1O7B"
FT STRAND 109..115
FT /evidence="ECO:0007829|PDB:2PF5"
FT STRAND 123..128
FT /evidence="ECO:0007829|PDB:2PF5"
FT STRAND 137..139
FT /evidence="ECO:0007829|PDB:2WNO"
FT STRAND 141..147
FT /evidence="ECO:0007829|PDB:2WNO"
FT TURN 149..152
FT /evidence="ECO:0007829|PDB:2WNO"
FT STRAND 160..166
FT /evidence="ECO:0007829|PDB:2WNO"
FT STRAND 172..181
FT /evidence="ECO:0007829|PDB:2WNO"
FT STRAND 190..209
FT /evidence="ECO:0007829|PDB:2WNO"
FT STRAND 211..213
FT /evidence="ECO:0007829|PDB:2WNO"
FT STRAND 221..230
FT /evidence="ECO:0007829|PDB:2WNO"
FT STRAND 239..247
FT /evidence="ECO:0007829|PDB:2WNO"
SQ SEQUENCE 277 AA; 31203 MW; E2B3AEB76353A782 CRC64;
MIILIYLFLL LWEDTQGWGF KDGIFHNSIW LERAAGVYHR EARSGKYKLT YAEAKAVCEF
EGGHLATYKQ LEAARKIGFH VCAAGWMAKG RVGYPIVKPG PNCGFGKTGI IDYGIRLNRS
ERWDAYCYNP HAKECGGVFT DPKQIFKSPG FPNEYEDNQI CYWHIRLKYG QRIHLSFLDF
DLEDDPGCLA DYVEIYDSYD DVHGFVGRYC GDELPDDIIS TGNVMTLKFL SDASVTAGGF
QIKYVAMDPV SKSSQGKNTS TTSTGNKNFL AGRFSHL
