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Protein

Tumor necrosis factor ligand superfamily member 12

Gene

TNFSF12

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Binds to FN14 and possibly also to TNRFSF12/APO3. Weak inducer of apoptosis in some cell types. Mediates NF-kappa-B activation. Promotes angiogenesis and the proliferation of endothelial cells. Also involved in induction of inflammatory cytokines. Promotes IL8 secretion.2 Publications

GO - Molecular functioni

  • cytokine activity Source: UniProtKB
  • receptor binding Source: ProtInc

GO - Biological processi

  • angiogenesis Source: UniProtKB-KW
  • apoptotic process Source: ProtInc
  • apoptotic signaling pathway Source: UniProtKB
  • cell differentiation Source: UniProtKB-KW
  • endothelial cell migration Source: UniProtKB
  • extrinsic apoptotic signaling pathway Source: Ensembl
  • immune response Source: InterPro
  • positive regulation of angiogenesis Source: UniProtKB
  • positive regulation of endothelial cell proliferation Source: UniProtKB
  • positive regulation of extrinsic apoptotic signaling pathway Source: UniProtKB
  • positive regulation of protein catabolic process Source: MGI
  • signal transduction Source: ProtInc
  • tumor necrosis factor-mediated signaling pathway Source: Reactome
Complete GO annotation...

Keywords - Molecular functioni

Cytokine, Developmental protein

Keywords - Biological processi

Angiogenesis, Apoptosis, Differentiation

Enzyme and pathway databases

BioCyciZFISH:ENSG00000161954-MONOMER.
ReactomeiR-HSA-5668541. TNFR2 non-canonical NF-kB pathway.
R-HSA-5676594. TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway.

Names & Taxonomyi

Protein namesi
Recommended name:
Tumor necrosis factor ligand superfamily member 12
Alternative name(s):
APO3 ligand
TNF-related weak inducer of apoptosis
Short name:
TWEAK
Cleaved into the following 2 chains:
Gene namesi
Name:TNFSF12
Synonyms:APO3L, DR3LG
ORF Names:UNQ181/PRO207
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 17

Organism-specific databases

HGNCiHGNC:11927. TNFSF12.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 21CytoplasmicSequence analysisAdd BLAST21
Transmembranei22 – 42Helical; Signal-anchor for type II membrane proteinSequence analysisAdd BLAST21
Topological domaini43 – 249ExtracellularSequence analysisAdd BLAST207

GO - Cellular componenti

  • extracellular region Source: Reactome
  • extracellular space Source: UniProtKB
  • integral component of plasma membrane Source: ProtInc
  • perinuclear region of cytoplasm Source: UniProtKB
  • plasma membrane Source: Reactome
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane, Secreted

Pathology & Biotechi

Organism-specific databases

DisGeNETi407977.
8742.
MalaCardsiTNFSF12.
OpenTargetsiENSG00000239697.
ENSG00000248871.
Orphaneti1572. Common variable immunodeficiency.
PharmGKBiPA162406662.
PA36620.

Polymorphism and mutation databases

BioMutaiTNFSF12.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000345201 – 249Tumor necrosis factor ligand superfamily member 12, membrane formAdd BLAST249
ChainiPRO_000003452194 – 249Tumor necrosis factor ligand superfamily member 12, secreted formAdd BLAST156

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi139N-linked (GlcNAc...)1
Disulfide bondi191 ↔ 2101 Publication

Post-translational modificationi

The soluble form derives from the membrane form by proteolytic processing.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei93 – 94Cleavage2

Keywords - PTMi

Cleavage on pair of basic residues, Disulfide bond, Glycoprotein

Proteomic databases

PaxDbiO43508.
PeptideAtlasiO43508.
PRIDEiO43508.

PTM databases

iPTMnetiO43508.
PhosphoSitePlusiO43508.

Expressioni

Tissue specificityi

Highly expressed in adult heart, pancreas, skeletal muscle, brain, colon, small intestine, lung, ovary, prostate, spleen, lymph node, appendix and peripheral blood lymphocytes. Low expression in kidney, testis, liver, placenta, thymus and bone marrow. Also detected in fetal kidney, liver, lung and brain.

Gene expression databases

BgeeiENSG00000239697.
ExpressionAtlasiO43508. baseline and differential.
GenevisibleiO43508. HS.

Organism-specific databases

HPAiHPA004863.
HPA052967.

Interactioni

Subunit structurei

Homotrimer (Probable). Interacts with the angiogenic factor AGGF1/VG5Q.Curated2 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
TNFRSF12AQ9NP842EBI-6932080,EBI-2851995
tnfrsf12aQ6SIX72EBI-6932080,EBI-8445678From a different organism.

GO - Molecular functioni

  • cytokine activity Source: UniProtKB
  • receptor binding Source: ProtInc

Protein-protein interaction databases

BioGridi114279. 6 interactors.
IntActiO43508. 6 interactors.
MINTiMINT-8415042.
STRINGi9606.ENSP00000451451.

Structurei

Secondary structure

1249
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi108 – 113Combined sources6
Beta strandi133 – 135Combined sources3
Beta strandi143 – 146Combined sources4
Turni148 – 150Combined sources3
Beta strandi153 – 155Combined sources3
Beta strandi159 – 173Combined sources15
Beta strandi175 – 183Combined sources9
Beta strandi186 – 193Combined sources8
Beta strandi205 – 218Combined sources14
Beta strandi223 – 227Combined sources5
Turni238 – 240Combined sources3
Beta strandi241 – 247Combined sources7

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4HT1X-ray2.50T97-249[»]
ProteinModelPortaliO43508.
SMRiO43508.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Sequence similaritiesi

Belongs to the tumor necrosis factor family.Curated

Keywords - Domaini

Signal-anchor, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiENOG410II60. Eukaryota.
ENOG410Y4KC. LUCA.
GeneTreeiENSGT00530000063837.
HOGENOMiHOG000134435.
HOVERGENiHBG055510.
InParanoidiO43508.
KOiK05474.
OMAiNPLRYDC.
OrthoDBiEOG091G0MIB.
PhylomeDBiO43508.
TreeFamiTF332331.

Family and domain databases

Gene3Di2.60.120.40. 1 hit.
InterProiIPR006052. TNF_dom.
IPR008983. Tumour_necrosis_fac-like_dom.
[Graphical view]
PfamiPF00229. TNF. 1 hit.
[Graphical view]
SMARTiSM00207. TNF. 1 hit.
[Graphical view]
SUPFAMiSSF49842. SSF49842. 1 hit.
PROSITEiPS50049. TNF_2. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: O43508-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MAARRSQRRR GRRGEPGTAL LVPLALGLGL ALACLGLLLA VVSLGSRASL
60 70 80 90 100
SAQEPAQEEL VAEEDQDPSE LNPQTEESQD PAPFLNRLVR PRRSAPKGRK
110 120 130 140 150
TRARRAIAAH YEVHPRPGQD GAQAGVDGTV SGWEEARINS SSPLRYNRQI
160 170 180 190 200
GEFIVTRAGL YYLYCQVHFD EGKAVYLKLD LLVDGVLALR CLEEFSATAA
210 220 230 240
SSLGPQLRLC QVSGLLALRP GSSLRIRTLP WAHLKAAPFL TYFGLFQVH
Length:249
Mass (Da):27,216
Last modified:June 1, 1998 - v1
Checksum:iE660843361C28EBA
GO
Isoform TWE-PRIL (identifier: O43508-2) [UniParc]FASTAAdd to basket
Also known as: TNFSF12-TNFSF13

The sequence of this isoform differs from the canonical sequence as follows:
     167-249: VHFDEGKAVY...LTYFGLFQVH → SSDALEAWEN...HGTFLGFVKL

Note: Based on a readthrough transcript which may produce a TWE-PRIL (TNFSF12-TNFSF13) fusion protein. Expressed at protein level in primary T-lymphocytes and monocytic cell lines.
Show »
Length:330
Mass (Da):36,589
Checksum:iFC6F3BCA29C029AE
GO

Sequence cautioni

The sequence AAH19047 differs from that shown. Reason: Frameshift at position 125.Curated

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_045245167 – 249VHFDE…LFQVH → SSDALEAWENGERSRKRRAV LTQKQKKQHSVLHLVPINAT SKDDSDVTEVMWQPALRRGR GLQAQGYGVRIQDAGVYLLY SQVLFQDVTFTMGQVVSREG QGRQETLFRCIRSMPSHPDR AYNSCYSAGVFHLHQGDILS VIIPRARAKLNLSPHGTFLG FVKL in isoform TWE-PRIL. 1 PublicationAdd BLAST83

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF030099 mRNA. Translation: AAC51923.1.
AF055872 mRNA. Translation: AAC39724.1.
AY081051 mRNA. Translation: AAL90443.1.
AY358870 mRNA. Translation: AAQ89229.1.
AC016876 Genomic DNA. No translation available.
BC019047 mRNA. Translation: AAH19047.1. Frameshift.
CCDSiCCDS11109.1. [O43508-1]
RefSeqiNP_003800.1. NM_003809.2. [O43508-1]
NP_742086.1. NM_172089.3. [O43508-2]
UniGeneiHs.54673.

Genome annotation databases

EnsembliENST00000293825; ENSP00000293825; ENSG00000239697. [O43508-1]
GeneIDi407977.
8742.
KEGGihsa:407977.
hsa:8742.

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF030099 mRNA. Translation: AAC51923.1.
AF055872 mRNA. Translation: AAC39724.1.
AY081051 mRNA. Translation: AAL90443.1.
AY358870 mRNA. Translation: AAQ89229.1.
AC016876 Genomic DNA. No translation available.
BC019047 mRNA. Translation: AAH19047.1. Frameshift.
CCDSiCCDS11109.1. [O43508-1]
RefSeqiNP_003800.1. NM_003809.2. [O43508-1]
NP_742086.1. NM_172089.3. [O43508-2]
UniGeneiHs.54673.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4HT1X-ray2.50T97-249[»]
ProteinModelPortaliO43508.
SMRiO43508.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi114279. 6 interactors.
IntActiO43508. 6 interactors.
MINTiMINT-8415042.
STRINGi9606.ENSP00000451451.

PTM databases

iPTMnetiO43508.
PhosphoSitePlusiO43508.

Polymorphism and mutation databases

BioMutaiTNFSF12.

Proteomic databases

PaxDbiO43508.
PeptideAtlasiO43508.
PRIDEiO43508.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000293825; ENSP00000293825; ENSG00000239697. [O43508-1]
GeneIDi407977.
8742.
KEGGihsa:407977.
hsa:8742.

Organism-specific databases

CTDi407977.
8742.
DisGeNETi407977.
8742.
GeneCardsiTNFSF12.
HGNCiHGNC:11927. TNFSF12.
HPAiHPA004863.
HPA052967.
MalaCardsiTNFSF12.
MIMi602695. gene.
neXtProtiNX_O43508.
OpenTargetsiENSG00000239697.
ENSG00000248871.
Orphaneti1572. Common variable immunodeficiency.
PharmGKBiPA162406662.
PA36620.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410II60. Eukaryota.
ENOG410Y4KC. LUCA.
GeneTreeiENSGT00530000063837.
HOGENOMiHOG000134435.
HOVERGENiHBG055510.
InParanoidiO43508.
KOiK05474.
OMAiNPLRYDC.
OrthoDBiEOG091G0MIB.
PhylomeDBiO43508.
TreeFamiTF332331.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000161954-MONOMER.
ReactomeiR-HSA-5668541. TNFR2 non-canonical NF-kB pathway.
R-HSA-5676594. TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway.

Miscellaneous databases

GeneWikiiTNFSF12.
TNFSF12-TNFSF13.
PROiO43508.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000239697.
ExpressionAtlasiO43508. baseline and differential.
GenevisibleiO43508. HS.

Family and domain databases

Gene3Di2.60.120.40. 1 hit.
InterProiIPR006052. TNF_dom.
IPR008983. Tumour_necrosis_fac-like_dom.
[Graphical view]
PfamiPF00229. TNF. 1 hit.
[Graphical view]
SMARTiSM00207. TNF. 1 hit.
[Graphical view]
SUPFAMiSSF49842. SSF49842. 1 hit.
PROSITEiPS50049. TNF_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiTNF12_HUMAN
AccessioniPrimary (citable) accession number: O43508
Secondary accession number(s): Q8IZK7, Q8WUZ7
Entry historyi
Integrated into UniProtKB/Swiss-Prot: June 6, 2002
Last sequence update: June 1, 1998
Last modified: November 30, 2016
This is version 150 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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, Complete proteome, Reference proteome

Documents

  1. Human chromosome 17
    Human chromosome 17: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  4. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.