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O14788

- TNF11_HUMAN

UniProt

O14788 - TNF11_HUMAN

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Protein

Tumor necrosis factor ligand superfamily member 11

Gene

TNFSF11

Organism
Homo sapiens (Human)
Status
Reviewed - 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.1 Publication

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sitei139 – 1402CleavageBy similarity

GO - Molecular functioni

  1. cytokine activity Source: UniProtKB
  2. tumor necrosis factor receptor binding Source: UniProtKB
  3. tumor necrosis factor receptor superfamily binding Source: BHF-UCL

GO - Biological processi

  1. activation of JUN kinase activity Source: Ensembl
  2. bone resorption Source: Ensembl
  3. calcium ion homeostasis Source: Ensembl
  4. cytokine-mediated signaling pathway Source: BHF-UCL
  5. ERK1 and ERK2 cascade Source: Ensembl
  6. immune response Source: UniProtKB
  7. mammary gland alveolus development Source: Ensembl
  8. mammary gland epithelial cell proliferation Source: Ensembl
  9. monocyte chemotaxis Source: BHF-UCL
  10. organ morphogenesis Source: Ensembl
  11. ossification Source: Ensembl
  12. osteoclast differentiation Source: UniProtKB
  13. osteoclast proliferation Source: Ensembl
  14. positive regulation of bone resorption Source: UniProtKB
  15. positive regulation of corticotropin-releasing hormone secretion Source: BHF-UCL
  16. positive regulation of ERK1 and ERK2 cascade via TNFSF11-mediated signaling Source: BHF-UCL
  17. positive regulation of fever generation by positive regulation of prostaglandin secretion Source: BHF-UCL
  18. positive regulation of homotypic cell-cell adhesion Source: BHF-UCL
  19. positive regulation of I-kappaB kinase/NF-kappaB signaling Source: Ensembl
  20. positive regulation of intracellular signal transduction Source: BHF-UCL
  21. positive regulation of JNK cascade Source: Ensembl
  22. positive regulation of MAP kinase activity Source: BHF-UCL
  23. positive regulation of NF-kappaB transcription factor activity Source: BHF-UCL
  24. positive regulation of osteoclast development Source: Ensembl
  25. positive regulation of osteoclast differentiation Source: UniProtKB
  26. positive regulation of protein kinase B signaling Source: Ensembl
  27. positive regulation of sequence-specific DNA binding transcription factor activity Source: BHF-UCL
  28. positive regulation of T cell activation Source: BHF-UCL
  29. positive regulation of transcription from RNA polymerase II promoter Source: BHF-UCL
  30. protein homooligomerization Source: Ensembl
  31. TNFSF11-mediated signaling pathway Source: BHF-UCL
  32. tumor necrosis factor-mediated signaling pathway Source: BHF-UCL
Complete GO annotation...

Keywords - Molecular functioni

Cytokine, Developmental protein, Receptor

Keywords - Biological processi

Differentiation

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
ProteomesiUP000005640: Chromosome 13

Organism-specific databases

HGNCiHGNC:11926. TNFSF11.

Subcellular locationi

Isoform 2 : Cytoplasm By similarity

GO - Cellular componenti

  1. cytoplasm Source: UniProtKB-KW
  2. extracellular region Source: UniProtKB
  3. extracellular space Source: UniProtKB-KW
  4. integral component of plasma membrane Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane, Secreted

Pathology & Biotechi

Involvement in diseasei

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.1 Publication
Note: The disease is caused by mutations affecting the gene represented in this entry.
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti199 – 1991M → K in OPTB2. 1 Publication
VAR_037424

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi223 – 2231R → A: Reduces affinity for TNFRSF11B. 1 Publication
Mutagenesisi257 – 2571K → A: Reduces affinity for TNFRSF11B. 1 Publication

Keywords - Diseasei

Disease mutation, Osteopetrosis

Organism-specific databases

MIMi259710. phenotype.
Orphaneti667. Autosomal recessive malignant osteopetrosis.
PharmGKBiPA36619.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 317317Tumor necrosis factor ligand superfamily member 11, membrane formPRO_0000034514Add
BLAST
Chaini140 – 317178Tumor necrosis factor ligand superfamily member 11, soluble formBy similarityPRO_0000034515Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Glycosylationi171 – 1711N-linked (GlcNAc...)Sequence Analysis
Glycosylationi198 – 1981N-linked (GlcNAc...)Sequence Analysis

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

Keywords - PTMi

Glycoprotein

Proteomic databases

PaxDbiO14788.
PRIDEiO14788.

PTM databases

PhosphoSiteiO14788.

Miscellaneous databases

PMAP-CutDBO14788.

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

BgeeiO14788.
CleanExiHS_TNFSF11.
ExpressionAtlasiO14788. baseline and differential.
GenevestigatoriO14788.

Organism-specific databases

HPAiCAB009193.

Interactioni

Subunit structurei

Homotrimer (Probable). Interacts with TNFRSF11B.1 PublicationCurated

Protein-protein interaction databases

BioGridi114160. 26 interactions.
IntActiO14788. 16 interactions.
MINTiMINT-8247611.
STRINGi9606.ENSP00000239849.

Structurei

Secondary structure

1
317
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Beta strandi165 – 1706Combined sources
Beta strandi182 – 1843Combined sources
Beta strandi187 – 1915Combined sources
Beta strandi194 – 2029Combined sources
Beta strandi205 – 2084Combined sources
Beta strandi212 – 22514Combined sources
Beta strandi227 – 2293Combined sources
Beta strandi235 – 24814Combined sources
Beta strandi253 – 26311Combined sources
Beta strandi269 – 28315Combined sources
Beta strandi287 – 2948Combined sources
Helixi296 – 2983Combined sources
Turni303 – 3053Combined sources
Beta strandi306 – 3149Combined sources

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
3URFX-ray2.70A162-317[»]
ProteinModelPortaliO14788.
SMRiO14788. Positions 162-317.
ModBaseiSearch...
MobiDBiSearch...

Topological domain

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini1 – 4747CytoplasmicSequence AnalysisAdd
BLAST
Topological domaini69 – 317249ExtracellularSequence AnalysisAdd
BLAST

Transmembrane

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Transmembranei48 – 6821Helical; Signal-anchor for type II membrane proteinSequence AnalysisAdd
BLAST

Family & Domainsi

Sequence similaritiesi

Belongs to the tumor necrosis factor family.Curated

Keywords - Domaini

Signal-anchor, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiNOG40842.
GeneTreeiENSGT00530000063443.
HOGENOMiHOG000132981.
HOVERGENiHBG054257.
InParanoidiO14788.
KOiK05473.
OMAiANECIAL.
OrthoDBiEOG7V4B0Q.
PhylomeDBiO14788.
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. Align

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)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti194 – 1941A → G in AAC51762. (PubMed:9312132)Curated

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti199 – 1991M → K in OPTB2. 1 Publication
VAR_037424

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 7373Missing in isoform 2. 2 PublicationsVSP_006447Add
BLAST
Alternative sequencei1 – 4747Missing in isoform 3. 1 PublicationVSP_006446Add
BLAST

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
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]
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.
UCSCiuc001uyt.2. human. [O14788-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
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 .
CCDSi CCDS9384.1. [O14788-1 ]
CCDS9385.1. [O14788-2 ]
RefSeqi NP_003692.1. NM_003701.3. [O14788-1 ]
NP_143026.1. NM_033012.3. [O14788-2 ]
UniGenei Hs.333791.

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
Entry Method Resolution (Å) Chain Positions PDBsum
3URF X-ray 2.70 A 162-317 [» ]
ProteinModelPortali O14788.
SMRi O14788. Positions 162-317.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 114160. 26 interactions.
IntActi O14788. 16 interactions.
MINTi MINT-8247611.
STRINGi 9606.ENSP00000239849.

Chemistry

ChEMBLi CHEMBL2364162.
DrugBanki DB06643. Denosumab.
DB00480. Lenalidomide.

PTM databases

PhosphoSitei O14788.

Proteomic databases

PaxDbi O14788.
PRIDEi O14788.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENST00000239849 ; ENSP00000239849 ; ENSG00000120659 . [O14788-3 ]
ENST00000358545 ; ENSP00000351347 ; ENSG00000120659 . [O14788-2 ]
ENST00000398795 ; ENSP00000381775 ; ENSG00000120659 . [O14788-1 ]
ENST00000405262 ; ENSP00000384042 ; ENSG00000120659 . [O14788-2 ]
ENST00000544862 ; ENSP00000444913 ; ENSG00000120659 . [O14788-2 ]
GeneIDi 8600.
KEGGi hsa:8600.
UCSCi uc001uyt.2. human. [O14788-1 ]

Organism-specific databases

CTDi 8600.
GeneCardsi GC13P043136.
HGNCi HGNC:11926. TNFSF11.
HPAi CAB009193.
MIMi 259710. phenotype.
602642. gene.
neXtProti NX_O14788.
Orphaneti 667. Autosomal recessive malignant osteopetrosis.
PharmGKBi PA36619.
GenAtlasi Search...

Phylogenomic databases

eggNOGi NOG40842.
GeneTreei ENSGT00530000063443.
HOGENOMi HOG000132981.
HOVERGENi HBG054257.
InParanoidi O14788.
KOi K05473.
OMAi ANECIAL.
OrthoDBi EOG7V4B0Q.
PhylomeDBi O14788.
TreeFami TF332169.

Miscellaneous databases

GeneWikii RANKL.
GenomeRNAii 8600.
NextBioi 32221.
PMAP-CutDB O14788.
PROi O14788.
SOURCEi Search...

Gene expression databases

Bgeei O14788.
CleanExi HS_TNFSF11.
ExpressionAtlasi O14788. baseline and differential.
Genevestigatori O14788.

Family and domain databases

Gene3Di 2.60.120.40. 1 hit.
InterProi IPR006052. TNF_dom.
IPR017355. TNF_ligand_10/11.
IPR008983. Tumour_necrosis_fac-like_dom.
[Graphical view ]
Pfami PF00229. TNF. 1 hit.
[Graphical view ]
PIRSFi PIRSF038013. TNF10_TNF11. 1 hit.
SMARTi SM00207. TNF. 1 hit.
[Graphical view ]
SUPFAMi SSF49842. SSF49842. 1 hit.
PROSITEi PS50049. TNF_2. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  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. 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. Cited for: VARIANT OPTB2 LYS-199.

Entry informationi

Entry nameiTNF11_HUMAN
AccessioniPrimary (citable) accession number: O14788
Secondary accession number(s): O14723, Q96Q17, Q9P2Q3
Entry historyi
Integrated into UniProtKB/Swiss-Prot: January 24, 2001
Last sequence update: January 1, 1998
Last modified: October 29, 2014
This is version 139 of the entry and version 1 of the sequence. [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

External Data

Dasty 3