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O14788

- TNF11_HUMAN

UniProt

O14788 - TNF11_HUMAN

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
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    • History
      Entry version 138 (01 Oct 2014)
      Sequence version 1 (01 Jan 1998)
      Previous versions | rss
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    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 differentiation Source: UniProtKB
    25. positive regulation of protein kinase B signaling Source: Ensembl
    26. positive regulation of sequence-specific DNA binding transcription factor activity Source: BHF-UCL
    27. positive regulation of T cell activation Source: BHF-UCL
    28. positive regulation of transcription from RNA polymerase II promoter Source: BHF-UCL
    29. protein homooligomerization Source: Ensembl
    30. TNFSF11-mediated signaling pathway Source: BHF-UCL
    31. tumor necrosis factor-mediated signaling pathway Source: BHF-UCL

    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-SubCell
    2. extracellular region Source: UniProtKB
    3. extracellular space Source: UniProtKB-KW
    4. integral component of plasma membrane Source: UniProtKB

    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

    ArrayExpressiO14788.
    BgeeiO14788.
    CleanExiHS_TNFSF11.
    GenevestigatoriO14788.

    Organism-specific databases

    HPAiCAB009193.

    Interactioni

    Subunit structurei

    Homotrimer Probable. Interacts with TNFRSF11B.1 PublicationCurated

    Protein-protein interaction databases

    BioGridi114160. 20 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 – 1706
    Beta strandi182 – 1843
    Beta strandi187 – 1915
    Beta strandi194 – 2029
    Beta strandi205 – 2084
    Beta strandi212 – 22514
    Beta strandi227 – 2293
    Beta strandi235 – 24814
    Beta strandi253 – 26311
    Beta strandi269 – 28315
    Beta strandi287 – 2948
    Helixi296 – 2983
    Turni303 – 3053
    Beta strandi306 – 3149

    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.
    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

    MRRASRDYTK YLRGSEEMGG GPGAPHEGPL HAPPPPAPHQ PPAASRSMFV    50
    ALLGLGLGQV VCSVALFFYF RAQMDPNRIS EDGTHCIYRI LRLHENADFQ 100
    DTTLESQDTK LIPDSCRRIK QAFQGAVQKE LQHIVGSQHI RAEKAMVDGS 150
    WLDLAKRSKL EAQPFAHLTI NATDIPSGSH KVSLSSWYHD RGWAKISNMT 200
    FSNGKLIVNQ DGFYYLYANI CFRHHETSGD LATEYLQLMV YVTKTSIKIP 250
    SSHTLMKGGS TKYWSGNSEF HFYSINVGGF FKLRSGEEIS IEVSNPSLLD 300
    PDQDATYFGA FKVRDID 317
    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. [O14788-1]
    ENST00000358545; ENSP00000351347; ENSG00000120659. [O14788-2]
    ENST00000398795; ENSP00000381775; ENSG00000120659. [O14788-2]
    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. 20 interactions.
    IntActi O14788. 16 interactions.
    MINTi MINT-8247611.
    STRINGi 9606.ENSP00000239849.

    Chemistry

    ChEMBLi CHEMBL2364162.

    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 . [O14788-1 ]
    ENST00000358545 ; ENSP00000351347 ; ENSG00000120659 . [O14788-2 ]
    ENST00000398795 ; ENSP00000381775 ; ENSG00000120659 . [O14788-2 ]
    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.
    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

    ArrayExpressi O14788.
    Bgeei O14788.
    CleanExi HS_TNFSF11.
    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

    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 1, 2014
    This is version 138 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