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Protein

Tumor necrosis factor ligand superfamily member 12

Gene

TNFSF12

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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
  • signaling receptor binding Source: ProtInc
  • tumor necrosis factor receptor binding Source: InterPro

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

Keywordsi

Molecular functionCytokine, Developmental protein
Biological processAngiogenesis, Apoptosis, Differentiation

Enzyme and pathway databases

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

EuPathDBiHostDB:ENSG00000239697.10
HGNCiHGNC:11927 TNFSF12
MIMi602695 gene
neXtProtiNX_O43508

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

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

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...) asparagine1
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

PeptideAtlasiO43508
PRIDEiO43508
ProteomicsDBi49000

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

Show more details

GO - Molecular functioni

  • cytokine activity Source: UniProtKB
  • signaling receptor binding Source: ProtInc
  • tumor necrosis factor receptor binding Source: InterPro

Protein-protein interaction databases

BioGridi114279, 7 interactors
IntActiO43508, 7 interactors
MINTiO43508

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
OMAiTAWTWRQ
OrthoDBiEOG091G0MIB
PhylomeDBiO43508
TreeFamiTF332331

Family and domain databases

Gene3Di2.60.120.40, 1 hit
InterProiView protein in InterPro
IPR006052 TNF_dom
IPR008983 Tumour_necrosis_fac-like_dom
PfamiView protein in Pfam
PF00229 TNF, 1 hit
SMARTiView protein in SMART
SM00207 TNF, 1 hit
SUPFAMiSSF49842 SSF49842, 1 hit
PROSITEiView protein in PROSITE
PS50049 TNF_2, 1 hit

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

Similar proteinsi

Entry informationi

Entry nameiTNF12_HUMAN
AccessioniPrimary (citable) accession number: O43508
Secondary accession number(s): Q8IZK7, Q8WUZ7
Entry historyiIntegrated into UniProtKB/Swiss-Prot: June 6, 2002
Last sequence update: June 1, 1998
Last modified: June 20, 2018
This is version 161 of the entry and version 1 of the sequence. See 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

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