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O14788 (TNF11_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 135. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Tumor necrosis factor ligand superfamily member 11
Alternative name(s):
Osteoclast differentiation factor
Short name=ODF
Osteoprotegerin ligand
Short name=OPGL
Receptor activator of nuclear factor kappa-B ligand
Short name=RANKL
TNF-related activation-induced cytokine
Short name=TRANCE
CD_antigen=CD254
Gene names
Name:TNFSF11
Synonyms:OPGL, RANKL, TRANCE
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length317 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Cytokine that binds to TNFRSF11B/OPG and to TNFRSF11A/RANK. Osteoclast differentiation and activation factor. Augments the ability of dendritic cells to stimulate naive T-cell proliferation. May be an important regulator of interactions between T-cells and dendritic cells and may play a role in the regulation of the T-cell-dependent immune response. May also play an important role in enhanced bone-resorption in humoral hypercalcemia of malignancy. Ref.7

Subunit structure

Homotrimer Probable. Interacts with TNFRSF11B. Ref.7

Subcellular location

Isoform 1: Cell membrane; Single-pass type II membrane protein.

Isoform 3: Cell membrane; Single-pass type II membrane protein.

Isoform 2: Cytoplasm By similarity.

Tumor necrosis factor ligand superfamily member 11, soluble form: Secreted By similarity.

Tissue specificity

Highest in the peripheral lymph nodes, weak in spleen, peripheral blood Leukocytes, bone marrow, heart, placenta, skeletal muscle, stomach and thyroid.

Induction

Up-regulated by T-cell receptor stimulation.

Post-translational modification

The soluble form of isoform 1 derives from the membrane form by proteolytic processing By similarity. The cleavage may be catalyzed by ADAM17.

Involvement in disease

Osteopetrosis, autosomal recessive 2 (OPTB2) [MIM:259710]: A rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. Osteopetrosis occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Recessive osteopetrosis commonly manifests in early infancy with macrocephaly, feeding difficulties, evolving blindness and deafness, bone marrow failure, severe anemia, and hepatosplenomegaly. Deafness and blindness are generally thought to represent effects of pressure on nerves. OPTB2 is characterized by paucity of osteoclasts, suggesting a molecular defect in osteoclast development.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.8

Sequence similarities

Belongs to the tumor necrosis factor family.

Ontologies

Keywords
   Biological processDifferentiation
   Cellular componentCell membrane
Cytoplasm
Membrane
Secreted
   Coding sequence diversityAlternative splicing
   DiseaseDisease mutation
Osteopetrosis
   DomainSignal-anchor
Transmembrane
Transmembrane helix
   Molecular functionCytokine
Developmental protein
Receptor
   PTMGlycoprotein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processERK1 and ERK2 cascade

Inferred from electronic annotation. Source: Ensembl

TNFSF11-mediated signaling pathway

Inferred from direct assay PubMed 18606301. Source: BHF-UCL

activation of JUN kinase activity

Inferred from electronic annotation. Source: Ensembl

bone resorption

Inferred from electronic annotation. Source: Ensembl

calcium ion homeostasis

Inferred from electronic annotation. Source: Ensembl

cytokine-mediated signaling pathway

Inferred from direct assay PubMed 15248232. Source: BHF-UCL

immune response

Non-traceable author statement Ref.6. Source: UniProtKB

mammary gland alveolus development

Inferred from electronic annotation. Source: Ensembl

mammary gland epithelial cell proliferation

Inferred from electronic annotation. Source: Ensembl

monocyte chemotaxis

Inferred from direct assay PubMed 15248232. Source: BHF-UCL

organ morphogenesis

Inferred from electronic annotation. Source: Ensembl

ossification

Inferred from electronic annotation. Source: Ensembl

osteoclast differentiation

Non-traceable author statement Ref.2. Source: UniProtKB

osteoclast proliferation

Inferred from electronic annotation. Source: Ensembl

positive regulation of ERK1 and ERK2 cascade via TNFSF11-mediated signaling

Inferred from direct assay PubMed 18606301. Source: BHF-UCL

positive regulation of I-kappaB kinase/NF-kappaB signaling

Inferred from electronic annotation. Source: Ensembl

positive regulation of JNK cascade

Inferred from electronic annotation. Source: Ensembl

positive regulation of MAP kinase activity

Inferred from direct assay PubMed 15304486. Source: BHF-UCL

positive regulation of NF-kappaB transcription factor activity

Inferred from direct assay Ref.1. Source: BHF-UCL

positive regulation of T cell activation

Inferred from direct assay Ref.1. Source: BHF-UCL

positive regulation of bone resorption

Inferred from direct assay PubMed 17241109. Source: UniProtKB

positive regulation of corticotropin-releasing hormone secretion

Inferred from sequence or structural similarity PubMed 19940926. Source: BHF-UCL

positive regulation of fever generation by positive regulation of prostaglandin secretion

Inferred from sequence or structural similarity PubMed 19940926. Source: BHF-UCL

positive regulation of homotypic cell-cell adhesion

Inferred from direct assay Ref.1. Source: BHF-UCL

positive regulation of intracellular signal transduction

Inferred from direct assay PubMed 15248232. Source: BHF-UCL

positive regulation of osteoclast differentiation

Inferred from direct assay PubMed 17241109. Source: UniProtKB

positive regulation of protein kinase B signaling

Inferred from electronic annotation. Source: Ensembl

positive regulation of sequence-specific DNA binding transcription factor activity

Inferred from sequence or structural similarity PubMed 19940926. Source: BHF-UCL

positive regulation of transcription from RNA polymerase II promoter

Inferred from direct assay PubMed 15304486. Source: BHF-UCL

protein homooligomerization

Inferred from electronic annotation. Source: Ensembl

tumor necrosis factor-mediated signaling pathway

Inferred from sequence or structural similarity PubMed 19940926. Source: BHF-UCL

   Cellular_componentcytoplasm

Inferred from electronic annotation. Source: UniProtKB-SubCell

extracellular region

Non-traceable author statement Ref.4Ref.2. Source: UniProtKB

extracellular space

Inferred from electronic annotation. Source: UniProtKB-KW

integral component of plasma membrane

Non-traceable author statement Ref.6. Source: UniProtKB

   Molecular_functioncytokine activity

Non-traceable author statement Ref.2. Source: UniProtKB

tumor necrosis factor receptor binding

Non-traceable author statement Ref.6Ref.1. Source: UniProtKB

tumor necrosis factor receptor superfamily binding

Inferred by curator PubMed 19940926. Source: BHF-UCL

Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: O14788-1)

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 2 (identifier: O14788-2)

Also known as: SODF;

The sequence of this isoform differs from the canonical sequence as follows:
     1-73: Missing.
Isoform 3 (identifier: O14788-3)

The sequence of this isoform differs from the canonical sequence as follows:
     1-47: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 317317Tumor necrosis factor ligand superfamily member 11, membrane form
PRO_0000034514
Chain140 – 317178Tumor necrosis factor ligand superfamily member 11, soluble form By similarity
PRO_0000034515

Regions

Topological domain1 – 4747Cytoplasmic Potential
Transmembrane48 – 6821Helical; Signal-anchor for type II membrane protein; Potential
Topological domain69 – 317249Extracellular Potential

Sites

Site139 – 1402Cleavage By similarity

Amino acid modifications

Glycosylation1711N-linked (GlcNAc...) Potential
Glycosylation1981N-linked (GlcNAc...) Potential

Natural variations

Alternative sequence1 – 7373Missing in isoform 2.
VSP_006447
Alternative sequence1 – 4747Missing in isoform 3.
VSP_006446
Natural variant1991M → K in OPTB2. Ref.8
VAR_037424

Experimental info

Mutagenesis2231R → A: Reduces affinity for TNFRSF11B. Ref.7
Mutagenesis2571K → A: Reduces affinity for TNFRSF11B. Ref.7
Sequence conflict1941A → G in AAC51762. Ref.6

Secondary structure

............................ 317
Helix Strand Turn

Details...

Sequences

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

Last modified January 1, 1998. Version 1.
Checksum: 766176446348097F

FASTA31735,478
        10         20         30         40         50         60 
MRRASRDYTK YLRGSEEMGG GPGAPHEGPL HAPPPPAPHQ PPAASRSMFV ALLGLGLGQV 

        70         80         90        100        110        120 
VCSVALFFYF RAQMDPNRIS EDGTHCIYRI LRLHENADFQ DTTLESQDTK LIPDSCRRIK 

       130        140        150        160        170        180 
QAFQGAVQKE LQHIVGSQHI RAEKAMVDGS WLDLAKRSKL EAQPFAHLTI NATDIPSGSH 

       190        200        210        220        230        240 
KVSLSSWYHD RGWAKISNMT FSNGKLIVNQ DGFYYLYANI CFRHHETSGD LATEYLQLMV 

       250        260        270        280        290        300 
YVTKTSIKIP SSHTLMKGGS TKYWSGNSEF HFYSINVGGF FKLRSGEEIS IEVSNPSLLD 

       310 
PDQDATYFGA FKVRDID 

« Hide

Isoform 2 (SODF) [UniParc].

Checksum: C827590684B6B83C
Show »

FASTA24427,690
Isoform 3 [UniParc].

Checksum: 5C7754CE32E6F368
Show »

FASTA27030,523

References

« Hide 'large scale' references
[1]"A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function."
Anderson D.M., Maraskovsky E., Billingsley W.L., Dougall W.C., Tometsko M.E., Roux E.R., Teepe M.C., DuBose R.F., Cosman D., Galibert L.
Nature 390:175-179(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Tissue: Bone marrow and Peripheral blood.
[2]"Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation."
Lacey D.L., Timms E., Tan H.-L., Kelley M.J., Dunstan C.R., Burgess T., Elliott R., Colombero A., Elliott G., Scully S., Hsu H., Sullivan J., Hawkins N., Davy E., Capparelli C., Eli A., Qian Y.-X., Kaufman S. expand/collapse author list , Sarosi I., Shalhoub V., Senaldi G., Guo J., Delaney J., Boyle W.J.
Cell 93:165-176(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Tissue: Lymph node.
[3]"Determination of human RANKL isoforms."
Ikeda T., Kuroyama H., Hirokawa K.
Submitted (JUN-2001) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 3).
[4]"Cancer cells responsible for humoral hypercalcemia express mRNA encoding a secreted form of ODF/TRANCE that induces osteoclast formation."
Nagai M., Kyakumoto S., Sato N.
Biochem. Biophys. Res. Commun. 269:532-536(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
Tissue: Tongue.
[5]"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: Lung.
[6]"TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells."
Wong B.R., Rho J., Arron J., Robinson E., Orlinick J., Chao M., Kalachikov S., Cayani E., Bartlett F.S. III, Frankel W.N., Lee S.Y., Choi Y.
J. Biol. Chem. 272:25190-25194(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 73-317.
Tissue: Thymocyte.
[7]"Crystal structure of human RANKL complexed with its decoy receptor osteoprotegerin."
Luan X., Lu Q., Jiang Y., Zhang S., Wang Q., Yuan H., Zhao W., Wang J., Wang X.
J. Immunol. 189:245-252(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 162-317 IN COMPLEX WITH TNFRSF11B, FUNCTION, MUTAGENESIS OF ARG-223 AND LYS-257, INTERACTION WITH TNFRSF11B.
[8]"Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL."
Sobacchi C., Frattini A., Guerrini M.M., Abinun M., Pangrazio A., Susani L., Bredius R., Mancini G., Cant A., Bishop N., Grabowski P., Del Fattore A., Messina C., Errigo G., Coxon F.P., Scott D.I., Teti A., Rogers M.J. expand/collapse author list , Vezzoni P., Villa A., Helfrich M.H.
Nat. Genet. 39:960-962(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT OPTB2 LYS-199.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF019047 mRNA. Translation: AAB86811.1.
AF053712 mRNA. Translation: AAC39731.1.
AB064269 mRNA. Translation: BAB79694.1.
AB061227 mRNA. Translation: BAB71768.1.
AB064270 mRNA. Translation: BAB79695.1.
AB037599 mRNA. Translation: BAA90488.1.
BC074823 mRNA. Translation: AAH74823.1.
BC074890 mRNA. Translation: AAH74890.1.
AF013171 mRNA. Translation: AAC51762.1.
RefSeqNP_003692.1. NM_003701.3.
NP_143026.1. NM_033012.3.
UniGeneHs.333791.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
3URFX-ray2.70A162-317[»]
ProteinModelPortalO14788.
SMRO14788. Positions 162-317.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid114160. 20 interactions.
IntActO14788. 16 interactions.
MINTMINT-8247611.
STRING9606.ENSP00000239849.

Chemistry

ChEMBLCHEMBL2364162.

PTM databases

PhosphoSiteO14788.

Proteomic databases

PaxDbO14788.
PRIDEO14788.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000239849; ENSP00000239849; ENSG00000120659. [O14788-1]
ENST00000358545; ENSP00000351347; ENSG00000120659. [O14788-2]
ENST00000398795; ENSP00000381775; ENSG00000120659. [O14788-2]
ENST00000405262; ENSP00000384042; ENSG00000120659. [O14788-2]
ENST00000544862; ENSP00000444913; ENSG00000120659. [O14788-2]
GeneID8600.
KEGGhsa:8600.
UCSCuc001uyt.2. human. [O14788-1]

Organism-specific databases

CTD8600.
GeneCardsGC13P043136.
HGNCHGNC:11926. TNFSF11.
HPACAB009193.
MIM259710. phenotype.
602642. gene.
neXtProtNX_O14788.
Orphanet667. Autosomal recessive malignant osteopetrosis.
PharmGKBPA36619.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG40842.
HOGENOMHOG000132981.
HOVERGENHBG054257.
InParanoidO14788.
KOK05473.
OMADIPSGSH.
OrthoDBEOG7V4B0Q.
PhylomeDBO14788.
TreeFamTF332169.

Gene expression databases

ArrayExpressO14788.
BgeeO14788.
CleanExHS_TNFSF11.
GenevestigatorO14788.

Family and domain databases

Gene3D2.60.120.40. 1 hit.
InterProIPR006052. TNF_dom.
IPR017355. TNF_ligand_10/11.
IPR008983. Tumour_necrosis_fac-like_dom.
[Graphical view]
PfamPF00229. TNF. 1 hit.
[Graphical view]
PIRSFPIRSF038013. TNF10_TNF11. 1 hit.
SMARTSM00207. TNF. 1 hit.
[Graphical view]
SUPFAMSSF49842. SSF49842. 1 hit.
PROSITEPS50049. TNF_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GeneWikiRANKL.
GenomeRNAi8600.
NextBio32221.
PMAP-CutDBO14788.
PROO14788.
SOURCESearch...

Entry information

Entry nameTNF11_HUMAN
AccessionPrimary (citable) accession number: O14788
Secondary accession number(s): O14723, Q96Q17, Q9P2Q3
Entry history
Integrated into UniProtKB/Swiss-Prot: January 24, 2001
Last sequence update: January 1, 1998
Last modified: April 16, 2014
This is version 135 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 polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 13

Human chromosome 13: entries, gene names and cross-references to MIM

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