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Protein

Tumor necrosis factor ligand superfamily member 11

Gene

TNFSF11

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

Functioni

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 (PubMed:22664871). Induces osteoclastogenesis by activating multiple signaling pathways in osteoclast precursor cells, chief among which is induction of long lasting oscillations in the intracellular concentration of Ca (2+) resulting in the activation of NFATC1, which translocates to the nucleus and induces osteoclast-specific gene transcription to allow differentiation of osteoclasts. During osteoclast differentiation, in a TMEM64 and ATP2A2-dependent manner induces activation of CREB1 and mitochondrial ROS generation necessary for proper osteoclast generation (By similarity).By similarity1 Publication

GO - Molecular functioni

  • cytokine activity Source: BHF-UCL
  • tumor necrosis factor receptor binding Source: UniProtKB
  • tumor necrosis factor receptor superfamily binding Source: BHF-UCL

GO - Biological processi

Keywordsi

Molecular functionCytokine, Developmental protein, Receptor
Biological processDifferentiation

Enzyme and pathway databases

ReactomeiR-HSA-5668541. TNFR2 non-canonical NF-kB pathway.
R-HSA-5669034. TNFs bind their physiological receptors.
R-HSA-5676594. TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway.
SIGNORiO14788.

Names & Taxonomyi

Protein namesi
Recommended 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
Cleaved into the following 2 chains:
Gene namesi
Name:TNFSF11
Synonyms:OPGL, RANKL, TRANCE
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 13

Organism-specific databases

EuPathDBiHostDB:ENSG00000120659.14.
HGNCiHGNC:11926. TNFSF11.

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 – 47CytoplasmicSequence analysisAdd BLAST47
Transmembranei48 – 68Helical; Signal-anchor for type II membrane proteinSequence analysisAdd BLAST21
Topological domaini69 – 317ExtracellularSequence analysisAdd BLAST249

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane, Secreted

Pathology & Biotechi

Involvement in diseasei

Osteopetrosis, autosomal recessive 2 (OPTB2)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA 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.
See also OMIM:259710
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_037424199M → K in OPTB2. 1 PublicationCorresponds to variant dbSNP:rs121909072Ensembl.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi223R → A: Reduces affinity for TNFRSF11B. 1 Publication1
Mutagenesisi257K → A: Reduces affinity for TNFRSF11B. 1 Publication1

Keywords - Diseasei

Disease mutation, Osteopetrosis

Organism-specific databases

DisGeNETi8600.
MalaCardsiTNFSF11.
MIMi259710. phenotype.
OpenTargetsiENSG00000120659.
Orphaneti667. Autosomal recessive malignant osteopetrosis.
PharmGKBiPA36619.

Chemistry databases

ChEMBLiCHEMBL2364162.
DrugBankiDB06643. Denosumab.
DB00480. Lenalidomide.
DB11582. Thiocolchicoside.

Polymorphism and mutation databases

BioMutaiTNFSF11.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000345141 – 317Tumor necrosis factor ligand superfamily member 11, membrane formAdd BLAST317
ChainiPRO_0000034515140 – 317Tumor necrosis factor ligand superfamily member 11, soluble formBy similarityAdd BLAST178

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi171N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi198N-linked (GlcNAc...) asparagineSequence analysis1

Post-translational modificationi

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

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei139 – 140CleavageBy similarity2

Keywords - PTMi

Glycoprotein

Proteomic databases

PaxDbiO14788.
PeptideAtlasiO14788.
PRIDEiO14788.

PTM databases

iPTMnetiO14788.
PhosphoSitePlusiO14788.

Miscellaneous databases

PMAP-CutDBiO14788.

Expressioni

Tissue specificityi

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

Inductioni

Up-regulated by T-cell receptor stimulation.

Gene expression databases

BgeeiENSG00000120659.
CleanExiHS_TNFSF11.
ExpressionAtlasiO14788. baseline and differential.
GenevisibleiO14788. HS.

Organism-specific databases

HPAiCAB009193.
HPA045142.

Interactioni

Subunit structurei

Homotrimer (By similarity). Interacts with TNFRSF11B (PubMed:22664871). Interacts with TNFRSF11A. Interacts with FBN1 (via N-terminal domain) in a Ca(+2)-dependent manner (By similarity).By similarity1 Publication

GO - Molecular functioni

  • cytokine activity Source: BHF-UCL
  • tumor necrosis factor receptor binding Source: UniProtKB
  • tumor necrosis factor receptor superfamily binding Source: BHF-UCL

Protein-protein interaction databases

BioGridi114160. 27 interactors.
IntActiO14788. 18 interactors.
MINTiMINT-8247611.
STRINGi9606.ENSP00000239849.

Structurei

Secondary structure

1317
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi165 – 170Combined sources6
Helixi172 – 174Combined sources3
Beta strandi178 – 180Combined sources3
Beta strandi182 – 184Combined sources3
Beta strandi187 – 191Combined sources5
Beta strandi194 – 202Combined sources9
Beta strandi205 – 208Combined sources4
Beta strandi212 – 225Combined sources14
Beta strandi227 – 229Combined sources3
Beta strandi235 – 248Combined sources14
Beta strandi253 – 263Combined sources11
Beta strandi269 – 283Combined sources15
Beta strandi287 – 294Combined sources8
Helixi296 – 298Combined sources3
Turni303 – 305Combined sources3
Beta strandi306 – 314Combined sources9

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
3URFX-ray2.70A162-317[»]
5BNQX-ray2.80A158-317[»]
ProteinModelPortaliO14788.
SMRiO14788.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Sequence similaritiesi

Belongs to the tumor necrosis factor family.Curated

Keywords - Domaini

Signal-anchor, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiENOG410IEIS. Eukaryota.
ENOG410YGCE. LUCA.
GeneTreeiENSGT00530000063443.
HOGENOMiHOG000132981.
HOVERGENiHBG054257.
InParanoidiO14788.
KOiK05473.
OMAiQDATYFG.
OrthoDBiEOG091G0F3S.
PhylomeDBiO14788.
TreeFamiTF332169.

Family and domain databases

Gene3Di2.60.120.40. 1 hit.
InterProiView protein in InterPro
IPR006052. TNF_dom.
IPR017355. TNF_ligand_10/11.
IPR008983. Tumour_necrosis_fac-like_dom.
PfamiView protein in Pfam
PF00229. TNF. 1 hit.
PIRSFiPIRSF038013. TNF10_TNF11. 1 hit.
SMARTiView protein in SMART
SM00207. TNF. 1 hit.
SUPFAMiSSF49842. SSF49842. 1 hit.
PROSITEiView protein in PROSITE
PS50049. TNF_2. 1 hit.

Sequences (3)i

Sequence statusi: Complete.

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

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: O14788-1) [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
MRRASRDYTK YLRGSEEMGG GPGAPHEGPL HAPPPPAPHQ PPAASRSMFV
60 70 80 90 100
ALLGLGLGQV VCSVALFFYF RAQMDPNRIS EDGTHCIYRI LRLHENADFQ
110 120 130 140 150
DTTLESQDTK LIPDSCRRIK QAFQGAVQKE LQHIVGSQHI RAEKAMVDGS
160 170 180 190 200
WLDLAKRSKL EAQPFAHLTI NATDIPSGSH KVSLSSWYHD RGWAKISNMT
210 220 230 240 250
FSNGKLIVNQ DGFYYLYANI CFRHHETSGD LATEYLQLMV YVTKTSIKIP
260 270 280 290 300
SSHTLMKGGS TKYWSGNSEF HFYSINVGGF FKLRSGEEIS IEVSNPSLLD
310
PDQDATYFGA FKVRDID
Length:317
Mass (Da):35,478
Last modified:January 1, 1998 - v1
Checksum:i766176446348097F
GO
Isoform 2 (identifier: O14788-2) [UniParc]FASTAAdd to basket
Also known as: SODF

The sequence of this isoform differs from the canonical sequence as follows:
     1-73: Missing.

Show »
Length:244
Mass (Da):27,690
Checksum:iC827590684B6B83C
GO
Isoform 3 (identifier: O14788-3) [UniParc]FASTAAdd to basket

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

Show »
Length:270
Mass (Da):30,523
Checksum:i5C7754CE32E6F368
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti194A → G in AAC51762 (PubMed:9312132).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_037424199M → K in OPTB2. 1 PublicationCorresponds to variant dbSNP:rs121909072Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0064471 – 73Missing in isoform 2. 2 PublicationsAdd BLAST73
Alternative sequenceiVSP_0064461 – 47Missing in isoform 3. 1 PublicationAdd BLAST47

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS9384.1. [O14788-1]
CCDS9385.1. [O14788-2]
RefSeqiNP_003692.1. NM_003701.3. [O14788-1]
NP_143026.1. NM_033012.3. [O14788-2]
XP_011533582.1. XM_011535280.2. [O14788-2]
XP_016876292.1. XM_017020803.1. [O14788-2]
UniGeneiHs.333791.

Genome annotation databases

EnsembliENST00000239849; ENSP00000239849; ENSG00000120659. [O14788-3]
ENST00000358545; ENSP00000351347; ENSG00000120659. [O14788-2]
ENST00000398795; ENSP00000381775; ENSG00000120659. [O14788-1]
ENST00000405262; ENSP00000384042; ENSG00000120659. [O14788-2]
ENST00000544862; ENSP00000444913; ENSG00000120659. [O14788-2]
GeneIDi8600.
KEGGihsa:8600.
UCSCiuc058wqy.1. human. [O14788-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiTNF11_HUMAN
AccessioniPrimary (citable) accession number: O14788
Secondary accession number(s): O14723, Q96Q17, Q9P2Q3
Entry historyiIntegrated into UniProtKB/Swiss-Prot: January 24, 2001
Last sequence update: January 1, 1998
Last modified: September 27, 2017
This is version 162 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

Documents

  1. Human cell differentiation molecules
    CD nomenclature of surface proteins of human leucocytes and list of entries
  2. Human chromosome 13
    Human chromosome 13: entries, gene names and cross-references to MIM
  3. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  4. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  5. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  6. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  7. SIMILARITY comments
    Index of protein domains and families