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Protein

Tumor necrosis factor ligand superfamily member 11

Gene

Tnfsf11

Organism
Mus musculus (Mouse)
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 (By similarity). 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 (PubMed:24039232). During osteoclast differentiation, in a TMEM64 and ATP2A2-dependent manner induces activation of CREB1 and mitochondrial ROS generation necessary for proper osteoclast generation (PubMed:23395171, PubMed:26644563).By similarity3 Publications

GO - Molecular functioni

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

GO - Biological processi

  • activation of JUN kinase activity Source: DFLAT
  • animal organ morphogenesis Source: MGI
  • bone resorption Source: MGI
  • calcium ion homeostasis Source: MGI
  • calcium-mediated signaling Source: UniProtKB
  • cytokine-mediated signaling pathway Source: MGI
  • ERK1 and ERK2 cascade Source: DFLAT
  • immune response Source: InterPro
  • lymph node development Source: MGI
  • mammary gland alveolus development Source: MGI
  • mammary gland epithelial cell proliferation Source: MGI
  • monocyte chemotaxis Source: MGI
  • ossification Source: MGI
  • osteoclast differentiation Source: UniProtKB
  • osteoclast proliferation Source: MGI
  • paracrine signaling Source: MGI
  • positive regulation of bone resorption Source: MGI
  • positive regulation of corticotropin-releasing hormone secretion Source: BHF-UCL
  • positive regulation of ERK1 and ERK2 cascade via TNFSF11-mediated signaling Source: MGI
  • positive regulation of fever generation by positive regulation of prostaglandin secretion Source: BHF-UCL
  • positive regulation of homotypic cell-cell adhesion Source: MGI
  • positive regulation of I-kappaB kinase/NF-kappaB signaling Source: MGI
  • positive regulation of intracellular signal transduction Source: MGI
  • positive regulation of JNK cascade Source: MGI
  • positive regulation of MAP kinase activity Source: MGI
  • positive regulation of NF-kappaB transcription factor activity Source: MGI
  • positive regulation of osteoclast development Source: MGI
  • positive regulation of osteoclast differentiation Source: MGI
  • positive regulation of phosphorylation Source: DFLAT
  • positive regulation of protein kinase B signaling Source: MGI
  • positive regulation of sequence-specific DNA binding transcription factor activity Source: BHF-UCL
  • positive regulation of T cell activation Source: MGI
  • positive regulation of transcription from RNA polymerase II promoter Source: MGI
  • protein homooligomerization Source: MGI
  • regulation of osteoclast differentiation Source: MGI
  • TNFSF11-mediated signaling pathway Source: MGI
  • tumor necrosis factor-mediated signaling pathway Source: BHF-UCL
Complete GO annotation...

Keywords - Molecular functioni

Cytokine, Developmental protein, Receptor

Keywords - Biological processi

Differentiation

Enzyme and pathway databases

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

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
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 14

Organism-specific databases

MGIiMGI:1100089. Tnfsf11.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 48CytoplasmicSequence analysisAdd BLAST48
Transmembranei49 – 69Helical; Signal-anchor for type II membrane proteinSequence analysisAdd BLAST21
Topological domaini70 – 316ExtracellularSequence analysisAdd BLAST247

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane, Secreted

Pathology & Biotechi

Involvement in diseasei

Deficiency in Tnfsf11 results in failure to form lobulo-alveolar mammary structures during pregnancy, resulting in death of newborns. Trance-deficient mice show severe osteopetrosis, with no osteoclasts, marrow spaces, or tooth eruption, and exhibit profound growth retardation at several skeletal sites, including the limbs, skull, and vertebrae and have marked chondrodysplasia, with thick, irregular growth plates and a relative increase in hypertrophic chondrocytes.

Chemistry databases

ChEMBLiCHEMBL3596084.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000345161 – 316Tumor necrosis factor ligand superfamily member 11, membrane formAdd BLAST316
ChainiPRO_0000034517139 – 316Tumor necrosis factor ligand superfamily member 11, soluble formAdd BLAST178

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi197N-linked (GlcNAc...)Sequence analysis1
Glycosylationi262N-linked (GlcNAc...)Sequence analysis1

Post-translational modificationi

N-glycosylated.1 Publication
The soluble form of isoform 1 derives from the membrane form by proteolytic processing. The cleavage may be catalyzed by ADAM17. A further shorter soluble form was observed.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei138 – 139Cleavage2

Keywords - PTMi

Glycoprotein

Proteomic databases

PaxDbiO35235.
PRIDEiO35235.

PTM databases

PhosphoSitePlusiO35235.

Miscellaneous databases

PMAP-CutDBQ3TWY5.

Expressioni

Tissue specificityi

Highly expressed in thymus and lymph nodes, but not in non-lymphoid tissues and is abundantly expressed in T-cells but not in B-cells. A high level expression is also seen in the trabecular bone and lung.

Gene expression databases

BgeeiENSMUSG00000022015.
GenevisibleiO35235. MM.

Interactioni

Subunit structurei

Homotrimer (PubMed:11581298, PubMed:11733492, PubMed:20483727). Interacts with TNFRSF11A and TNFRSF11B (PubMed:20483727, PubMed:23039992). Interacts with FBN1 (via N-terminal domain) in a Ca(+2)-dependent manner (PubMed:24039232).5 Publications

GO - Molecular functioni

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

Protein-protein interaction databases

DIPiDIP-59480N.
IntActiO35235. 1 interactor.
STRINGi10090.ENSMUSP00000022592.

Structurei

Secondary structure

1316
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi164 – 169Combined sources6
Helixi171 – 173Combined sources3
Beta strandi177 – 179Combined sources3
Beta strandi181 – 183Combined sources3
Beta strandi186 – 190Combined sources5
Beta strandi194 – 201Combined sources8
Beta strandi204 – 207Combined sources4
Beta strandi211 – 224Combined sources14
Helixi225 – 227Combined sources3
Beta strandi233 – 248Combined sources16
Beta strandi251 – 262Combined sources12
Beta strandi265 – 282Combined sources18
Beta strandi286 – 293Combined sources8
Helixi295 – 297Combined sources3
Turni302 – 304Combined sources3
Beta strandi305 – 313Combined sources9

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1IQAX-ray2.20A/B/C157-316[»]
1JTZX-ray2.60X/Y/Z156-316[»]
1S55X-ray1.90A/B/C161-316[»]
3ME2X-ray2.80A158-316[»]
3QBQX-ray2.50A/C157-316[»]
4E4DX-ray2.70X162-316[»]
4GIQX-ray2.70A158-316[»]
ProteinModelPortaliO35235.
SMRiO35235.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiO35235.

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.
InParanoidiO35235.
KOiK05473.
OMAiQHIRAEK.
OrthoDBiEOG091G0F3S.
TreeFamiTF332169.

Family and domain databases

Gene3Di2.60.120.40. 1 hit.
InterProiIPR006052. TNF_dom.
IPR017355. TNF_ligand_10/11.
IPR008983. Tumour_necrosis_fac-like_dom.
[Graphical view]
PfamiPF00229. TNF. 1 hit.
[Graphical view]
PIRSFiPIRSF038013. TNF10_TNF11. 1 hit.
SMARTiSM00207. TNF. 1 hit.
[Graphical view]
SUPFAMiSSF49842. SSF49842. 1 hit.
PROSITEiPS50049. TNF_2. 1 hit.
[Graphical view]

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: O35235-1) [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
MRRASRDYGK YLRSSEEMGS GPGVPHEGPL HPAPSAPAPA PPPAASRSMF
60 70 80 90 100
LALLGLGLGQ VVCSIALFLY FRAQMDPNRI SEDSTHCFYR ILRLHENADL
110 120 130 140 150
QDSTLESEDT LPDSCRRMKQ AFQGAVQKEL QHIVGPQRFS GAPAMMEGSW
160 170 180 190 200
LDVAQRGKPE AQPFAHLTIN AASIPSGSHK VTLSSWYHDR GWAKISNMTL
210 220 230 240 250
SNGKLRVNQD GFYYLYANIC FRHHETSGSV PTDYLQLMVY VVKTSIKIPS
260 270 280 290 300
SHNLMKGGST KNWSGNSEFH FYSINVGGFF KLRAGEEISI QVSNPSLLDP
310
DQDATYFGAF KVQDID
Length:316
Mass (Da):35,003
Last modified:July 27, 2011 - v2
Checksum:i8AF3825F92E0A786
GO
Isoform 2 (identifier: O35235-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     14-44: SSEEMGSGPGVPHEGPLHPAPSAPAPAPPPA → TP

Show »
Length:287
Mass (Da):32,293
Checksum:i09000919EB550530
GO
Isoform 3 (identifier: O35235-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-117: Missing.

Show »
Length:199
Mass (Da):22,150
Checksum:i401C13EB5E8CE166
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti99D → G in AAC71061 (PubMed:9312132).Curated1
Sequence conflicti99D → G in AAC40113 (PubMed:9568710).Curated1
Sequence conflicti99D → G in BAA25425 (PubMed:9520411).Curated1
Sequence conflicti99D → G in BAA36970 (PubMed:10196481).Curated1
Sequence conflicti99D → G in BAA97257 (PubMed:11250921).Curated1
Sequence conflicti99D → G in BAA97259 (PubMed:11250921).Curated1
Sequence conflicti141 – 143Missing in BAA36970 (PubMed:10196481).Curated3

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0064481 – 117Missing in isoform 3. 1 PublicationAdd BLAST117
Alternative sequenceiVSP_00644914 – 44SSEEM…APPPA → TP in isoform 2. 1 PublicationAdd BLAST31

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF013170 mRNA. Translation: AAC71061.1.
AF019048 mRNA. Translation: AAB86812.1.
AF053713 mRNA. Translation: AAC40113.1.
AB008426 mRNA. Translation: BAA25425.1.
AB022039 Genomic DNA. Translation: BAA36970.1.
AB032771 mRNA. Translation: BAA97257.1.
AB032772 mRNA. Translation: BAA97258.1.
AB036798 mRNA. Translation: BAA97259.1.
AK159498 mRNA. Translation: BAE35131.1.
CCDSiCCDS27294.1. [O35235-1]
RefSeqiNP_035743.2. NM_011613.3. [O35235-1]
UniGeneiMm.249221.

Genome annotation databases

EnsembliENSMUST00000022592; ENSMUSP00000022592; ENSMUSG00000022015. [O35235-1]
GeneIDi21943.
KEGGimmu:21943.
UCSCiuc007ush.1. mouse. [O35235-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF013170 mRNA. Translation: AAC71061.1.
AF019048 mRNA. Translation: AAB86812.1.
AF053713 mRNA. Translation: AAC40113.1.
AB008426 mRNA. Translation: BAA25425.1.
AB022039 Genomic DNA. Translation: BAA36970.1.
AB032771 mRNA. Translation: BAA97257.1.
AB032772 mRNA. Translation: BAA97258.1.
AB036798 mRNA. Translation: BAA97259.1.
AK159498 mRNA. Translation: BAE35131.1.
CCDSiCCDS27294.1. [O35235-1]
RefSeqiNP_035743.2. NM_011613.3. [O35235-1]
UniGeneiMm.249221.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1IQAX-ray2.20A/B/C157-316[»]
1JTZX-ray2.60X/Y/Z156-316[»]
1S55X-ray1.90A/B/C161-316[»]
3ME2X-ray2.80A158-316[»]
3QBQX-ray2.50A/C157-316[»]
4E4DX-ray2.70X162-316[»]
4GIQX-ray2.70A158-316[»]
ProteinModelPortaliO35235.
SMRiO35235.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

DIPiDIP-59480N.
IntActiO35235. 1 interactor.
STRINGi10090.ENSMUSP00000022592.

Chemistry databases

ChEMBLiCHEMBL3596084.

PTM databases

PhosphoSitePlusiO35235.

Proteomic databases

PaxDbiO35235.
PRIDEiO35235.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000022592; ENSMUSP00000022592; ENSMUSG00000022015. [O35235-1]
GeneIDi21943.
KEGGimmu:21943.
UCSCiuc007ush.1. mouse. [O35235-1]

Organism-specific databases

CTDi8600.
MGIiMGI:1100089. Tnfsf11.

Phylogenomic databases

eggNOGiENOG410IEIS. Eukaryota.
ENOG410YGCE. LUCA.
GeneTreeiENSGT00530000063443.
HOGENOMiHOG000132981.
HOVERGENiHBG054257.
InParanoidiO35235.
KOiK05473.
OMAiQHIRAEK.
OrthoDBiEOG091G0F3S.
TreeFamiTF332169.

Enzyme and pathway databases

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

Miscellaneous databases

ChiTaRSiTnfsf11. mouse.
EvolutionaryTraceiO35235.
PMAP-CutDBQ3TWY5.
PROiO35235.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000022015.
GenevisibleiO35235. MM.

Family and domain databases

Gene3Di2.60.120.40. 1 hit.
InterProiIPR006052. TNF_dom.
IPR017355. TNF_ligand_10/11.
IPR008983. Tumour_necrosis_fac-like_dom.
[Graphical view]
PfamiPF00229. TNF. 1 hit.
[Graphical view]
PIRSFiPIRSF038013. TNF10_TNF11. 1 hit.
SMARTiSM00207. TNF. 1 hit.
[Graphical view]
SUPFAMiSSF49842. SSF49842. 1 hit.
PROSITEiPS50049. TNF_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiTNF11_MOUSE
AccessioniPrimary (citable) accession number: O35235
Secondary accession number(s): O35306
, Q3TWY5, Q9JJK8, Q9JJK9, Q9R1Y0
Entry historyi
Integrated into UniProtKB/Swiss-Prot: January 24, 2001
Last sequence update: July 27, 2011
Last modified: November 30, 2016
This is version 159 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  3. 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.