UniProtKB - P98066 (TSG6_HUMAN)
Tumor necrosis factor-inducible gene 6 protein
TNFAIP6
Functioni
Major regulator of extracellular matrix organization during tissue remodeling (PubMed:18042364, PubMed:26823460, PubMed:15917224).
Catalyzes the transfer of a heavy chain (HC) from inter-alpha-inhibitor (I-alpha-I) complex to hyaluronan. Cleaves the ester bond between the C-terminus of the HC and GalNAc residue of the chondroitin sulfate chain in I-alpha-I complex followed by transesterification of the HC to hyaluronan. In the process, potentiates the antiprotease function of I-alpha-I complex through release of free bikunin (PubMed:20463016, PubMed:15917224, PubMed:16873769).
Acts as a catalyst in the formation of hyaluronan-HC oligomers and hyaluronan-rich matrix surrounding the cumulus cell-oocyte complex, a necessary step for oocyte fertilization (PubMed:26468290).
Assembles hyaluronan in pericellular matrices that serve as platforms for receptor clustering and signaling. Enables binding of hyaluronan deposited on the surface of macrophages to LYVE1 on lymphatic endothelium and facilitates macrophage extravasation. Alters hyaluronan binding to functionally latent CD44 on vascular endothelium, switching CD44 into an active state that supports leukocyte rolling (PubMed:26823460, PubMed:15060082).
Modulates the interaction of chemokines with extracellular matrix components and proteoglycans on endothelial cell surface, likely preventing chemokine gradient formation (PubMed:27044744).
In a negative feedback mechanism, may limit excessive neutrophil recruitment at inflammatory sites by antagonizing the association of CXCL8 with glycosaminoglycans on vascular endothelium (PubMed:24501198).
Has a role in osteogenesis and bone remodeling. Inhibits BMP2-dependent differentiation of mesenchymal stem cell to osteoblasts (PubMed:18586671, PubMed:16771708).
Protects against bone erosion during inflammation by inhibiting TNFSF11/RANKL-dependent osteoclast activation (PubMed:18586671).
11 PublicationspH dependencei
Sites
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Metal bindingi | 183 | CalciumCombined sources1 Publication | 1 | |
Metal bindingi | 191 | CalciumCombined sources1 Publication | 1 | |
Metal bindingi | 232 | CalciumCombined sources1 Publication | 1 | |
Metal bindingi | 234 | Calcium; via carbonyl oxygenCombined sources1 Publication | 1 | |
Metal bindingi | 235 | Calcium; via carbonyl oxygenCombined sources1 Publication | 1 |
GO - Molecular functioni
- calcium ion binding Source: UniProtKB
- carboxylic ester hydrolase activity Source: UniProtKB
- fibronectin binding Source: UniProtKB
- hyaluronic acid binding Source: UniProtKB
GO - Biological processi
- cell adhesion Source: UniProtKB-KW
- cell-cell signaling Source: ProtInc
- fibronectin fibril organization Source: UniProtKB
- hyaluronan metabolic process Source: UniProtKB
- inflammatory response Source: ProtInc
- negative regulation of BMP signaling pathway Source: UniProtKB
- negative regulation of inflammatory response Source: CACAO
- negative regulation of neutrophil chemotaxis Source: UniProtKB
- negative regulation of osteoblast differentiation Source: UniProtKB
- negative regulation of osteoclast differentiation Source: UniProtKB
- ovarian cumulus expansion Source: UniProtKB
- ovulation Source: Ensembl
- positive regulation of cell migration Source: Ensembl
- positive regulation of receptor clustering Source: UniProtKB
- signal transduction Source: ProtInc
Keywordsi
Molecular function | Hydrolase |
Biological process | Cell adhesion |
Ligand | Calcium, Metal-binding |
Enzyme and pathway databases
PathwayCommonsi | P98066 |
Reactomei | R-HSA-6798695, Neutrophil degranulation |
SignaLinki | P98066 |
SIGNORi | P98066 |
Names & Taxonomyi
Protein namesi | Recommended name: Tumor necrosis factor-inducible gene 6 protein (EC:3.1.1.-1 Publication)Alternative name(s): Hyaluronate-binding protein TNF-stimulated gene 6 protein Short name: TSG-61 Publication Tumor necrosis factor alpha-induced protein 6 Short name: TNF alpha-induced protein 6 |
Gene namesi | Name:TNFAIP6 Synonyms:TSG6 |
Organismi | Homo sapiens (Human) |
Taxonomic identifieri | 9606 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Proteomesi |
|
Organism-specific databases
HGNCi | HGNC:11898, TNFAIP6 |
MIMi | 600410, gene |
neXtProti | NX_P98066 |
VEuPathDBi | HostDB:ENSG00000123610 |
Subcellular locationi
Extracellular region or secreted
- Secreted 1 Publication
Extracellular region or secreted
- extracellular region Source: UniProtKB
- extracellular space Source: GO_Central
Other locations
- ficolin-1-rich granule lumen Source: Reactome
- tertiary granule lumen Source: Reactome
Keywords - Cellular componenti
SecretedPathology & Biotechi
Mutagenesis
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Mutagenesisi | 39 | H → K: Decreases binding of hyaluronan to CD44. Decreases hyaluronan-dependent lymphocyte rolling. 1 Publication | 1 | |
Mutagenesisi | 41 | E → K: Has no significant effect on hyaluronan binding to CD44 or hyaluronan-dependent lymphocyte rolling. 1 Publication | 1 | |
Mutagenesisi | 46 | K → Q: Abolishes binding to bikunin. 1 Publication | 1 | |
Mutagenesisi | 47 | Y → F: Abolishes binding to bikunin. Impairs binding to hyaluronan. Retains the ability to bind heavy chains but cannot transfer them onto hyaluronan. Impairs binding of hyaluronan to CD44. Decreases hyaluronan-dependent lymphocyte rolling. 3 Publications | 1 | |
Mutagenesisi | 48 | K → E: Decreases binding of hyaluronan to CD44. Decreases hyaluronan-dependent lymphocyte rolling. 1 Publication | 1 | |
Mutagenesisi | 55 | K → A: Decreases binding to heparin. Has normal binding to bikunin. Impairs binding to heparin; when associated with A-69 and A-76. Has no effect on CXCL8-induced neutrophil transmigration; when associated with A-69 and A-76. 2 Publications | 1 | |
Mutagenesisi | 64 | H → K: Increases binding of hyaluronan to CD44. Has no significant effect on hyaluronan-dependent lymphocyte rolling. 1 Publication | 1 | |
Mutagenesisi | 69 | K → A: Decreases binding to heparin. Has normal binding to bikunin. Impairs binding to heparin; when associated with A-55 and A-76. Has no effect on CXCL8-induced neutrophil transmigration; when associated with A-55 and A-76. 2 Publications | 1 | |
Mutagenesisi | 76 | K → A: Decreases binding to heparin. Has normal binding to bikunin. Impairs binding to heparin and decreases the potentiation effect toward bikunin antiprotease activity; when associated with A-55 and A-69. Has no effect on CXCL8-induced neutrophil transmigration; when associated with A-55 and A-69. 2 Publications | 1 | |
Mutagenesisi | 89 | K → A: Decreases binding to heparin. Has normal binding to bikunin. 1 Publication | 1 | |
Mutagenesisi | 94 | Y → F: Abolishes binding to bikunin. Has no effect on transesterification reaction. 2 Publications | 1 | |
Mutagenesisi | 105 | F → V: Impairs binding of hyaluronan to CD44. Decreases hyaluronan-dependent lymphocyte rolling. 1 Publication | 1 | |
Mutagenesisi | 113 | Y → F: Abolishes binding to bikunin. Impairs binding of hyaluronan to CD44. Decreases hyaluronan-dependent lymphocyte rolling. Has no effect on transesterification reaction. 3 Publications | 1 | |
Mutagenesisi | 183 | E → S: Reduces the binding affinity to calcium ions. Abolishes the interaction with heavy chain ITIH1. 1 Publication | 1 |
Organism-specific databases
DisGeNETi | 7130 |
OpenTargetsi | ENSG00000123610 |
PharmGKBi | PA36595 |
Miscellaneous databases
Pharosi | P98066, Tbio |
Chemistry databases
DrugBanki | DB00945, Acetylsalicylic acid DB00843, Donepezil DB08818, Hyaluronic acid |
Genetic variation databases
BioMutai | TNFAIP6 |
DMDMi | 68067717 |
PTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Signal peptidei | 1 – 17 | 1 PublicationAdd BLAST | 17 | |
ChainiPRO_0000026692 | 18 – 277 | Tumor necrosis factor-inducible gene 6 proteinAdd BLAST | 260 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Disulfide bondi | 58 ↔ 127 | PROSITE-ProRule annotation | ||
Disulfide bondi | 82 ↔ 103 | PROSITE-ProRule annotation | ||
Glycosylationi | 118 | N-linked (GlcNAc...) asparagineSequence analysis | 1 | |
Disulfide bondi | 135 ↔ 161 | PROSITE-ProRule annotation | ||
Disulfide bondi | 188 ↔ 210 | PROSITE-ProRule annotation | ||
Glycosylationi | 258 | N-linked (GlcNAc...) asparagineSequence analysis | 1 |
Post-translational modificationi
Keywords - PTMi
Disulfide bond, GlycoproteinProteomic databases
MassIVEi | P98066 |
PaxDbi | P98066 |
PeptideAtlasi | P98066 |
PRIDEi | P98066 |
ProteomicsDBi | 57783 |
PTM databases
GlyGeni | P98066, 2 sites |
iPTMneti | P98066 |
PhosphoSitePlusi | P98066 |
Expressioni
Tissue specificityi
Inductioni
Gene expression databases
Bgeei | ENSG00000123610, Expressed in layer of synovial tissue and 198 other tissues |
Genevisiblei | P98066, HS |
Organism-specific databases
HPAi | ENSG00000123610, Tissue enriched (urinary) |
Interactioni
Subunit structurei
Interacts (via Link domain) with inter-alpha-inhibitor (I-alpha-I) component bikunin (PubMed:15917224).
Interacts with ITIH2/HC2; this interaction is required for transesterification of the HC to hyaluronan (PubMed:20463016).
Interacts (via Link and CUB domains) with ITIH1 (PubMed:26468290). Chondroitin sulfate may be required for the stability of the complex (PubMed:7516184).
Interacts (via Link domain) with various C-X-C and C-C chemokines including PF4, CXCL8, CXCL11, CXCL12, CCL2, CCL7, CCL19, CCL21, and CCL27; this interaction interferes with chemokine binding to glycosaminoglycans (PubMed:24501198, PubMed:27044744).
Interacts (primarily via Link domain) with BMP2; this interaction is inhibited by hyaluronan (PubMed:16771708).
Interacts (via both Link and CUB domains) with TNFSF11 (PubMed:18586671).
Interacts (via CUB domain) with FN1 (via type III repeats 9-14); this interaction enhances fibronectin fibril assembly. TNFAIP6 may act as a bridging molecule between FN1 and THBS1 (PubMed:18042364).
9 PublicationsBinary interactionsi
P98066
GO - Molecular functioni
- fibronectin binding Source: UniProtKB
Protein-protein interaction databases
BioGRIDi | 112984, 25 interactors |
IntActi | P98066, 25 interactors |
STRINGi | 9606.ENSP00000243347 |
Miscellaneous databases
RNActi | P98066, protein |
Structurei
Secondary structure
3D structure databases
BMRBi | P98066 |
SMRi | P98066 |
ModBasei | Search... |
PDBe-KBi | Search... |
Miscellaneous databases
EvolutionaryTracei | P98066 |
Family & Domainsi
Domains and Repeats
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Domaini | 36 – 129 | LinkPROSITE-ProRule annotationAdd BLAST | 94 | |
Domaini | 135 – 247 | CUBPROSITE-ProRule annotationAdd BLAST | 113 |
Domaini
Keywords - Domaini
SignalPhylogenomic databases
eggNOGi | KOG1218, Eukaryota KOG3714, Eukaryota |
GeneTreei | ENSGT00940000157201 |
HOGENOMi | CLU_092089_0_0_1 |
InParanoidi | P98066 |
OMAi | YDDIHGF |
OrthoDBi | 934805at2759 |
PhylomeDBi | P98066 |
TreeFami | TF334173 |
Family and domain databases
CDDi | cd00041, CUB, 1 hit |
Gene3Di | 2.60.120.290, 1 hit 3.10.100.10, 1 hit |
InterProi | View protein in InterPro IPR016186, C-type_lectin-like/link_sf IPR016187, CTDL_fold IPR000859, CUB_dom IPR000538, Link_dom IPR035914, Sperma_CUB_dom_sf |
Pfami | View protein in Pfam PF00431, CUB, 1 hit PF00193, Xlink, 1 hit |
PRINTSi | PR01265, LINKMODULE |
SMARTi | View protein in SMART SM00042, CUB, 1 hit SM00445, LINK, 1 hit |
SUPFAMi | SSF49854, SSF49854, 1 hit SSF56436, SSF56436, 1 hit |
PROSITEi | View protein in PROSITE PS01180, CUB, 1 hit PS01241, LINK_1, 1 hit PS50963, LINK_2, 1 hit |
i Sequence
Sequence statusi: Complete.
: The displayed sequence is further processed into a mature form. Sequence processingi
10 20 30 40 50
MIILIYLFLL LWEDTQGWGF KDGIFHNSIW LERAAGVYHR EARSGKYKLT
60 70 80 90 100
YAEAKAVCEF EGGHLATYKQ LEAARKIGFH VCAAGWMAKG RVGYPIVKPG
110 120 130 140 150
PNCGFGKTGI IDYGIRLNRS ERWDAYCYNP HAKECGGVFT DPKQIFKSPG
160 170 180 190 200
FPNEYEDNQI CYWHIRLKYG QRIHLSFLDF DLEDDPGCLA DYVEIYDSYD
210 220 230 240 250
DVHGFVGRYC GDELPDDIIS TGNVMTLKFL SDASVTAGGF QIKYVAMDPV
260 270
SKSSQGKNTS TTSTGNKNFL AGRFSHL
Natural variant
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Natural variantiVAR_013005 | 144 | Q → R2 PublicationsCorresponds to variant dbSNP:rs1046668Ensembl. | 1 |
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | M31165 mRNA Translation: AAB00792.1 AJ421518 mRNA Translation: CAD13434.1 AJ419936 mRNA Translation: CAD12353.1 AC009311 Genomic DNA Translation: AAY15067.1 CH471058 Genomic DNA Translation: EAX11511.1 BC030205 mRNA Translation: AAH30205.1 |
CCDSi | CCDS2193.1 |
PIRi | A41735 |
RefSeqi | NP_009046.2, NM_007115.3 |
Genome annotation databases
Ensembli | ENST00000243347; ENSP00000243347; ENSG00000123610 |
GeneIDi | 7130 |
KEGGi | hsa:7130 |
MANE-Selecti | ENST00000243347.5; ENSP00000243347.3; NM_007115.4; NP_009046.2 |
UCSCi | uc002txk.3, human |
Similar proteinsi
Cross-referencesi
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | M31165 mRNA Translation: AAB00792.1 AJ421518 mRNA Translation: CAD13434.1 AJ419936 mRNA Translation: CAD12353.1 AC009311 Genomic DNA Translation: AAY15067.1 CH471058 Genomic DNA Translation: EAX11511.1 BC030205 mRNA Translation: AAH30205.1 |
CCDSi | CCDS2193.1 |
PIRi | A41735 |
RefSeqi | NP_009046.2, NM_007115.3 |
3D structure databases
Select the link destinations: PDBei RCSB PDBi PDBji Links Updated | PDB entry | Method | Resolution (Å) | Chain | Positions | PDBsum |
1O7B | NMR | - | T | 36-133 | [»] | |
1O7C | NMR | - | T | 36-133 | [»] | |
2N40 | NMR | - | A | 36-133 | [»] | |
2PF5 | X-ray | 1.90 | A/B/C/D/E | 36-133 | [»] | |
2WNO | X-ray | 2.30 | A | 129-277 | [»] | |
BMRBi | P98066 | |||||
SMRi | P98066 | |||||
ModBasei | Search... | |||||
PDBe-KBi | Search... |
Protein-protein interaction databases
BioGRIDi | 112984, 25 interactors |
IntActi | P98066, 25 interactors |
STRINGi | 9606.ENSP00000243347 |
Chemistry databases
DrugBanki | DB00945, Acetylsalicylic acid DB00843, Donepezil DB08818, Hyaluronic acid |
PTM databases
GlyGeni | P98066, 2 sites |
iPTMneti | P98066 |
PhosphoSitePlusi | P98066 |
Genetic variation databases
BioMutai | TNFAIP6 |
DMDMi | 68067717 |
Proteomic databases
MassIVEi | P98066 |
PaxDbi | P98066 |
PeptideAtlasi | P98066 |
PRIDEi | P98066 |
ProteomicsDBi | 57783 |
Protocols and materials databases
Antibodypediai | 33651, 195 antibodies from 32 providers |
DNASUi | 7130 |
Genome annotation databases
Ensembli | ENST00000243347; ENSP00000243347; ENSG00000123610 |
GeneIDi | 7130 |
KEGGi | hsa:7130 |
MANE-Selecti | ENST00000243347.5; ENSP00000243347.3; NM_007115.4; NP_009046.2 |
UCSCi | uc002txk.3, human |
Organism-specific databases
CTDi | 7130 |
DisGeNETi | 7130 |
GeneCardsi | TNFAIP6 |
HGNCi | HGNC:11898, TNFAIP6 |
HPAi | ENSG00000123610, Tissue enriched (urinary) |
MIMi | 600410, gene |
neXtProti | NX_P98066 |
OpenTargetsi | ENSG00000123610 |
PharmGKBi | PA36595 |
VEuPathDBi | HostDB:ENSG00000123610 |
GenAtlasi | Search... |
Phylogenomic databases
eggNOGi | KOG1218, Eukaryota KOG3714, Eukaryota |
GeneTreei | ENSGT00940000157201 |
HOGENOMi | CLU_092089_0_0_1 |
InParanoidi | P98066 |
OMAi | YDDIHGF |
OrthoDBi | 934805at2759 |
PhylomeDBi | P98066 |
TreeFami | TF334173 |
Enzyme and pathway databases
PathwayCommonsi | P98066 |
Reactomei | R-HSA-6798695, Neutrophil degranulation |
SignaLinki | P98066 |
SIGNORi | P98066 |
Miscellaneous databases
BioGRID-ORCSi | 7130, 10 hits in 1041 CRISPR screens |
ChiTaRSi | TNFAIP6, human |
EvolutionaryTracei | P98066 |
GeneWikii | TSG-6 |
GenomeRNAii | 7130 |
Pharosi | P98066, Tbio |
PROi | PR:P98066 |
RNActi | P98066, protein |
SOURCEi | Search... |
Gene expression databases
Bgeei | ENSG00000123610, Expressed in layer of synovial tissue and 198 other tissues |
Genevisiblei | P98066, HS |
Family and domain databases
CDDi | cd00041, CUB, 1 hit |
Gene3Di | 2.60.120.290, 1 hit 3.10.100.10, 1 hit |
InterProi | View protein in InterPro IPR016186, C-type_lectin-like/link_sf IPR016187, CTDL_fold IPR000859, CUB_dom IPR000538, Link_dom IPR035914, Sperma_CUB_dom_sf |
Pfami | View protein in Pfam PF00431, CUB, 1 hit PF00193, Xlink, 1 hit |
PRINTSi | PR01265, LINKMODULE |
SMARTi | View protein in SMART SM00042, CUB, 1 hit SM00445, LINK, 1 hit |
SUPFAMi | SSF49854, SSF49854, 1 hit SSF56436, SSF56436, 1 hit |
PROSITEi | View protein in PROSITE PS01180, CUB, 1 hit PS01241, LINK_1, 1 hit PS50963, LINK_2, 1 hit |
MobiDBi | Search... |
Entry informationi
Entry namei | TSG6_HUMAN | |
Accessioni | P98066Primary (citable) accession number: P98066 Secondary accession number(s): Q53TI7, Q8WWI9 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | February 1, 1996 |
Last sequence update: | June 21, 2005 | |
Last modified: | February 23, 2022 | |
This is version 188 of the entry and version 2 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Chordata Protein Annotation Program | |
Disclaimer | Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care. |
Miscellaneousi
Keywords - Technical termi
3D-structure, Direct protein sequencing, Reference proteomeDocuments
- Human chromosome 2
Human chromosome 2: entries, gene names and cross-references to MIM - Human entries with genetic variants
List of human entries with genetic variants - Human variants curated from literature reports
Index of human variants curated from literature reports - MIM cross-references
Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot - PDB cross-references
Index of Protein Data Bank (PDB) cross-references