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O43508 (TNF12_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 129. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (4) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Tumor necrosis factor ligand superfamily member 12
Alternative name(s):
APO3 ligand
TNF-related weak inducer of apoptosis
Short name=TWEAK
Gene names
Name:TNFSF12
Synonyms:APO3L, DR3LG
ORF Names:UNQ181/PRO207
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length249 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.7 Ref.10

Subunit structure

Homotrimer Probable. Interacts with the angiogenic factor AGGF1/VG5Q. Ref.8 Ref.10

Subcellular location

Cell membrane; Single-pass type II membrane protein Ref.3.

Tumor necrosis factor ligand superfamily member 12, secreted form: Secreted Ref.3.

Isoform TWE-PRIL: Cell membrane; Single-pass membrane protein Ref.3.

Tissue specificity

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.

Post-translational modification

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

Sequence similarities

Belongs to the tumor necrosis factor family.

Sequence caution

The sequence AAH19047.1 differs from that shown. Reason: Frameshift at position 125.

Ontologies

Keywords
   Biological processAngiogenesis
Apoptosis
Differentiation
   Cellular componentCell membrane
Membrane
Secreted
   Coding sequence diversityAlternative splicing
   DomainSignal-anchor
Transmembrane
Transmembrane helix
   Molecular functionCytokine
Developmental protein
   PTMCleavage on pair of basic residues
Disulfide bond
Glycoprotein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processangiogenesis

Inferred from electronic annotation. Source: UniProtKB-KW

apoptotic process

Traceable author statement Ref.2. Source: ProtInc

apoptotic signaling pathway

Traceable author statement PubMed 21525013. Source: UniProtKB

cell differentiation

Inferred from electronic annotation. Source: UniProtKB-KW

endothelial cell migration

Traceable author statement Ref.8. Source: UniProtKB

immune response

Inferred from electronic annotation. Source: InterPro

positive regulation of angiogenesis

Traceable author statement Ref.8. Source: UniProtKB

positive regulation of endothelial cell proliferation

Traceable author statement Ref.8. Source: UniProtKB

positive regulation of extrinsic apoptotic signaling pathway

Inferred from direct assay PubMed 21525013. Source: UniProtKB

signal transduction

Traceable author statement Ref.2. Source: ProtInc

   Cellular_componentextracellular space

Inferred from electronic annotation. Source: UniProtKB-KW

integral component of plasma membrane

Traceable author statement Ref.2. Source: ProtInc

perinuclear region of cytoplasm

Inferred from direct assay Ref.8. Source: UniProtKB

   Molecular_functioncytokine activity

Traceable author statement PubMed 21525013. Source: UniProtKB

protein binding

Inferred from physical interaction Ref.8. Source: UniProtKB

receptor binding

Traceable author statement Ref.2. Source: ProtInc

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

TNFRSF12AQ9NP842EBI-6932080,EBI-2851995
tnfrsf12aQ6SIX72EBI-6932080,EBI-8445678From a different organism.

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: O43508-1)

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.
Isoform TWE-PRIL (identifier: O43508-2)

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.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 249249Tumor necrosis factor ligand superfamily member 12, membrane form
PRO_0000034520
Chain94 – 249156Tumor necrosis factor ligand superfamily member 12, secreted form
PRO_0000034521

Regions

Topological domain1 – 2121Cytoplasmic Potential
Transmembrane22 – 4221Helical; Signal-anchor for type II membrane protein; Potential
Topological domain43 – 249207Extracellular Potential

Sites

Site93 – 942Cleavage

Amino acid modifications

Glycosylation1391N-linked (GlcNAc...)
Disulfide bond191 ↔ 210 Ref.10

Natural variations

Alternative sequence167 – 24983VHFDE…LFQVH → SSDALEAWENGERSRKRRAV LTQKQKKQHSVLHLVPINAT SKDDSDVTEVMWQPALRRGR GLQAQGYGVRIQDAGVYLLY SQVLFQDVTFTMGQVVSREG QGRQETLFRCIRSMPSHPDR AYNSCYSAGVFHLHQGDILS VIIPRARAKLNLSPHGTFLG FVKL in isoform TWE-PRIL.
VSP_045245

Secondary structure

........................ 249
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified June 1, 1998. Version 1.
Checksum: E660843361C28EBA

FASTA24927,216
        10         20         30         40         50         60 
MAARRSQRRR GRRGEPGTAL LVPLALGLGL ALACLGLLLA VVSLGSRASL SAQEPAQEEL 

        70         80         90        100        110        120 
VAEEDQDPSE LNPQTEESQD PAPFLNRLVR PRRSAPKGRK TRARRAIAAH YEVHPRPGQD 

       130        140        150        160        170        180 
GAQAGVDGTV SGWEEARINS SSPLRYNRQI GEFIVTRAGL YYLYCQVHFD EGKAVYLKLD 

       190        200        210        220        230        240 
LLVDGVLALR CLEEFSATAA SSLGPQLRLC QVSGLLALRP GSSLRIRTLP WAHLKAAPFL 


TYFGLFQVH 

« Hide

Isoform TWE-PRIL (TNFSF12-TNFSF13) [UniParc].

Checksum: FC6F3BCA29C029AE
Show »

FASTA33036,589

References

« Hide 'large scale' references
[1]"TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis."
Chicheportiche Y., Bourdon P.R., Xu H., Hsu Y.-M., Scott H., Hession C., Garcia I., Browning J.L.
J. Biol. Chem. 272:32401-32410(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), N-TERMINUS OF SOLUBLE FORM.
Tissue: Fetal liver and Tonsil.
[2]"Identification of a ligand for the death-domain-containing receptor Apo3."
Marsters S.A., Sheridan J.P., Pitti R.M., Brush J., Goddard A., Ashkenazi A.
Curr. Biol. 8:525-528(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Tissue: Fetal kidney.
[3]"An endogenous hybrid mRNA encodes TWE-PRIL, a functional cell surface TWEAK-APRIL fusion protein."
Pradet-Balade B., Medema J.P., Lopez-Fraga M., Lozano J.C., Kolfschoten G.M., Picard A., Martinez-A C., Garcia-Sanz J.A., Hahne M.
EMBO J. 21:5711-5720(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM TWE-PRIL), SUBCELLULAR LOCATION.
[4]"The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment."
Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J., Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P., Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E. expand/collapse author list , Heldens S., Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.
Genome Res. 13:2265-2270(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[5]"DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage."
Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R., Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A., Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J., Chang J.L. expand/collapse author list , Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J., DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D., Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A., Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.
Nature 440:1045-1049(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Tonsil.
[7]"TWEAK induces angiogenesis and proliferation of endothelial cells."
Lynch C.N., Wang Y.C., Lund J.K., Chen Y.-W., Leal J.A., Wiley S.R.
J. Biol. Chem. 274:8455-8459(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[8]"Identification of an angiogenic factor that when mutated causes susceptibility to Klippel-Trenaunay syndrome."
Tian X.-L., Kadaba R., You S.-A., Liu M., Timur A.A., Yang L., Chen Q., Szafranski P., Rao S., Wu L., Housman D.E., DiCorleto P.E., Driscoll D.J., Borrow J., Wang Q.
Nature 427:640-645(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH AGGF1/VG5Q.
[9]"TWEAK, a member of the TNF superfamily, is a multifunctional cytokine that binds the TweakR/Fn14 receptor."
Wiley S.R., Winkles J.A.
Cytokine Growth Factor Rev. 14:241-249(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[10]"Crystal structure of human TWEAK in complex with the Fab fragment of a neutralizing antibody reveals insights into receptor binding."
Lammens A., Baehner M., Kohnert U., Niewoehner J., von Proff L., Schraeml M., Lammens K., Hopfner K.P.
PLoS ONE 8:E62697-E62697(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 97-249 IN COMPLEX WITH THE FAB FRAGMENT OF A NEUTRALIZING ANTIBODY, FUNCTION, SUBUNIT, DISULFIDE BOND.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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.
CCDSCCDS11109.1. [O43508-1]
RefSeqNP_003800.1. NM_003809.2. [O43508-1]
NP_742086.1. NM_172089.3. [O43508-2]
UniGeneHs.54673.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
4HT1X-ray2.50T97-249[»]
ProteinModelPortalO43508.
SMRO43508. Positions 105-249.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid114279. 5 interactions.
IntActO43508. 5 interactions.
MINTMINT-8415042.
STRING9606.ENSP00000293826.

PTM databases

PhosphoSiteO43508.

Proteomic databases

PaxDbO43508.
PRIDEO43508.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000293825; ENSP00000293825; ENSG00000239697. [O43508-1]
ENST00000557233; ENSP00000451451; ENSG00000239697. [O43508-2]
GeneID407977.
8742.
KEGGhsa:407977.
hsa:8742.
UCSCuc002ghg.3. human. [O43508-1]
uc002ghi.1. human.

Organism-specific databases

CTD407977.
8742.
GeneCardsGC17P007452.
HGNCHGNC:11927. TNFSF12.
MIM602695. gene.
neXtProtNX_O43508.
Orphanet1572. Common variable immunodeficiency.
PharmGKBPA162406662.
PA36620.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG45253.
HOGENOMHOG000134435.
HOVERGENHBG055510.
KOK05474.
OMARIMSFIE.
OrthoDBEOG79KPGF.
PhylomeDBO43508.
TreeFamTF332331.

Gene expression databases

ArrayExpressO43508.
BgeeO43508.
GenevestigatorO43508.

Family and domain databases

Gene3D2.60.120.40. 1 hit.
InterProIPR006052. TNF_dom.
IPR008983. Tumour_necrosis_fac-like_dom.
[Graphical view]
PfamPF00229. TNF. 1 hit.
[Graphical view]
SMARTSM00207. TNF. 1 hit.
[Graphical view]
SUPFAMSSF49842. SSF49842. 1 hit.
PROSITEPS50049. TNF_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSTNFSF12-TNFSF13. human.
GeneWikiTNFSF12.
TNFSF12-TNFSF13.
NextBio108346.
PROO43508.
SOURCESearch...

Entry information

Entry nameTNF12_HUMAN
AccessionPrimary (citable) accession number: O43508
Secondary accession number(s): Q8IZK7, Q8WUZ7
Entry history
Integrated into UniProtKB/Swiss-Prot: June 6, 2002
Last sequence update: June 1, 1998
Last modified: July 9, 2014
This is version 129 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human chromosome 17

Human chromosome 17: entries, gene names and cross-references to MIM