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Q9Y6Q6 (TNR11_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 126. 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·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Tumor necrosis factor receptor superfamily member 11A
Alternative name(s):
Osteoclast differentiation factor receptor
Short name=ODFR
Receptor activator of NF-KB
CD_antigen=CD265
Gene names
Name:TNFRSF11A
Synonyms:RANK
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length616 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Receptor for TNFSF11/RANKL/TRANCE/OPGL; essential for RANKL-mediated osteoclastogenesis. Involved in the regulation of interactions between T-cells and dendritic cells. Ref.5

Subunit structure

Binds to the clefts between the subunits of the TNFSF11 ligand trimer to form a heterohexamer By similarity. Interacts with TRAF1, TRAF2, TRAF3, TRAF5 and TRAF6. Interacts (via cytoplasmic domain) with GAB2. Ref.6 Ref.7

Subcellular location

Isoform 1: Cell membrane; Single-pass type I membrane protein Ref.2.

Isoform RANK-e5a: Cell membrane; Single-pass type I membrane protein Ref.2.

Tissue specificity

Ubiquitous expression with high levels in skeletal muscle, thymus, liver, colon, small intestine and adrenal gland.

Involvement in disease

Familial expansile osteolysis (FEO) [MIM:174810]: Rare autosomal dominant bone disorder characterized by focal areas of increased bone remodeling. The osteolytic lesions develop usually in the long bones during early adulthood. FEO is often associated with early-onset deafness and loss of dentition.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.9

Paget disease of bone 2 (PDB2) [MIM:602080]: Bone-remodeling disorder with clinical similarities to FEO. Unlike FEO, however, affected individuals have involvement of the axial skeleton with lesions in the spine, pelvis and skull.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.9

Osteopetrosis, autosomal recessive 7 (OPTB7) [MIM:612301]: 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. OPTB7 is characterized by paucity of osteoclasts, suggesting a molecular defect in osteoclast development. OPTB7 is associated with hypogammaglobulinemia.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.10

Sequence similarities

Contains 4 TNFR-Cys repeats.

Sequence caution

The sequence BAD92999.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

Ontologies

Keywords
   Cellular componentCell membrane
Membrane
   Coding sequence diversityAlternative splicing
Polymorphism
   DiseaseDeafness
Disease mutation
Osteopetrosis
   DomainRepeat
Signal
Transmembrane
Transmembrane helix
   LigandMetal-binding
Sodium
   Molecular functionReceptor
   PTMDisulfide bond
Glycoprotein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processTNFSF11-mediated signaling pathway

Inferred from mutant phenotype Ref.10. Source: BHF-UCL

adaptive immune response

Inferred from mutant phenotype Ref.10. Source: BHF-UCL

cell-cell signaling

Traceable author statement Ref.1. Source: ProtInc

circadian temperature homeostasis

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

lymph node development

Inferred from electronic annotation. Source: Ensembl

mammary gland alveolus development

Inferred from electronic annotation. Source: Ensembl

monocyte chemotaxis

Non-traceable author statement PubMed 15248232. Source: BHF-UCL

ossification

Inferred from electronic annotation. Source: Ensembl

osteoclast differentiation

Inferred from mutant phenotype Ref.10. Source: BHF-UCL

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

Inferred from mutant phenotype Ref.10. Source: BHF-UCL

positive regulation of JUN kinase activity

Inferred from mutant phenotype PubMed 12296995. Source: BHF-UCL

positive regulation of NF-kappaB transcription factor activity

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

positive regulation of cell proliferation

Traceable author statement Ref.1. Source: ProtInc

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 sequence-specific DNA binding transcription factor activity

Inferred from direct assay PubMed 12296995. Source: BHF-UCL

response to cytokine

Inferred from mutant phenotype Ref.10. Source: BHF-UCL

response to interleukin-1

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

response to lipopolysaccharide

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

response to radiation

Inferred from electronic annotation. Source: Ensembl

response to tumor necrosis factor

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

signal transduction

Traceable author statement Ref.1. Source: ProtInc

tumor necrosis factor-mediated signaling pathway

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

   Cellular_componentexternal side of plasma membrane

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

integral component of membrane

Inferred from electronic annotation. Source: UniProtKB-KW

   Molecular_functioncytokine binding

Inferred from physical interaction Ref.1. Source: BHF-UCL

metal ion binding

Inferred from electronic annotation. Source: UniProtKB-KW

receptor activity

Traceable author statement Ref.1. Source: ProtInc

transmembrane signaling receptor activity

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

tumor necrosis factor-activated receptor activity

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

Complete GO annotation...

Alternative products

This entry describes 6 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q9Y6Q6-1)

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: Q9Y6Q6-2)

Also known as: delta7,8,9;

The sequence of this isoform differs from the canonical sequence as follows:
     206-522: Missing.
Isoform 3 (identifier: Q9Y6Q6-3)

Also known as: delta8,9;

The sequence of this isoform differs from the canonical sequence as follows:
     244-522: Missing.
Isoform 4 (identifier: Q9Y6Q6-4)

Also known as: delta9;

The sequence of this isoform differs from the canonical sequence as follows:
     263-263: S → M
     264-616: Missing.
Isoform 5 (identifier: Q9Y6Q6-5)

Also known as: exon9a;

The sequence of this isoform differs from the canonical sequence as follows:
     523-616: GNVTGNSNST...PVQEQGGAKA → D
Isoform RANK-e5a (identifier: Q9Y6Q6-6)

The sequence of this isoform differs from the canonical sequence as follows:
     143-157: LQLNKDTVCKPCLAG → C
Note: Reduced abilitity to bind RANKL and to activate NF-kappaB as compared to isoform 1.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2929 Potential
Chain30 – 616587Tumor necrosis factor receptor superfamily member 11A
PRO_0000034585

Regions

Topological domain30 – 212183Extracellular Potential
Transmembrane213 – 23321Helical; Potential
Topological domain234 – 616383Cytoplasmic Potential
Repeat34 – 6835TNFR-Cys 1
Repeat71 – 11242TNFR-Cys 2
Repeat114 – 15138TNFR-Cys 3
Repeat154 – 19441TNFR-Cys 4

Sites

Metal binding1331Sodium; via carbonyl oxygen By similarity
Metal binding1341Sodium; via carbonyl oxygen By similarity
Metal binding1601Sodium; via carbonyl oxygen By similarity

Amino acid modifications

Glycosylation1051N-linked (GlcNAc...) Potential
Glycosylation1741N-linked (GlcNAc...) Potential
Disulfide bond34 ↔ 46 By similarity
Disulfide bond47 ↔ 60 By similarity
Disulfide bond50 ↔ 68 By similarity
Disulfide bond71 ↔ 86 By similarity
Disulfide bond92 ↔ 112 By similarity
Disulfide bond114 ↔ 127 By similarity
Disulfide bond124 ↔ 126 By similarity
Disulfide bond133 ↔ 151 By similarity
Disulfide bond154 ↔ 169 By similarity
Disulfide bond175 ↔ 194 By similarity

Natural variations

Alternative sequence143 – 15715LQLNK…PCLAG → C in isoform RANK-e5a.
VSP_054179
Alternative sequence206 – 522317Missing in isoform 2.
VSP_046901
Alternative sequence244 – 522279Missing in isoform 3.
VSP_054180
Alternative sequence2631S → M in isoform 4.
VSP_054181
Alternative sequence264 – 616353Missing in isoform 4.
VSP_054182
Alternative sequence523 – 61694GNVTG…GGAKA → D in isoform 5.
VSP_054183
Natural variant211L → LALLLLCALL in PDB2.
VAR_011516
Natural variant211L → LLLCALL in FEO. Ref.9
VAR_011517
Natural variant531G → R in OPTB7; two patients with osteoclast-poor osteopetrosis. Ref.10
VAR_046788
Natural variant1291R → C in OPTB7; a patient with osteoclast-poor osteopetrosis. Ref.10
VAR_046789
Natural variant1411H → Y.
Corresponds to variant rs35211496 [ dbSNP | Ensembl ].
VAR_046790
Natural variant1701R → G in OPTB7; two siblings with osteoclast-poor osteopetrosis. Ref.10
VAR_046791
Natural variant1751C → R in OPTB7; two patients with osteoclast-poor osteopetrosis. Ref.10
VAR_046792
Natural variant1921A → V. Ref.9
Corresponds to variant rs1805034 [ dbSNP | Ensembl ].
VAR_011518
Natural variant2441A → S in OPTB7; one patient with osteoclast-poor osteopetrosis. Ref.10
VAR_046793

Secondary structure

... 616
Helix Strand Turn

Details...

Sequences

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

Last modified November 1, 1999. Version 1.
Checksum: E3DE9A7A08196F81

FASTA61666,034
        10         20         30         40         50         60 
MAPRARRRRP LFALLLLCAL LARLQVALQI APPCTSEKHY EHLGRCCNKC EPGKYMSSKC 

        70         80         90        100        110        120 
TTTSDSVCLP CGPDEYLDSW NEEDKCLLHK VCDTGKALVA VVAGNSTTPR RCACTAGYHW 

       130        140        150        160        170        180 
SQDCECCRRN TECAPGLGAQ HPLQLNKDTV CKPCLAGYFS DAFSSTDKCR PWTNCTFLGK 

       190        200        210        220        230        240 
RVEHHGTEKS DAVCSSSLPA RKPPNEPHVY LPGLIILLLF ASVALVAAII FGVCYRKKGK 

       250        260        270        280        290        300 
ALTANLWHWI NEACGRLSGD KESSGDSCVS THTANFGQQG ACEGVLLLTL EEKTFPEDMC 

       310        320        330        340        350        360 
YPDQGGVCQG TCVGGGPYAQ GEDARMLSLV SKTEIEEDSF RQMPTEDEYM DRPSQPTDQL 

       370        380        390        400        410        420 
LFLTEPGSKS TPPFSEPLEV GENDSLSQCF TGTQSTVGSE SCNCTEPLCR TDWTPMSSEN 

       430        440        450        460        470        480 
YLQKEVDSGH CPHWAASPSP NWADVCTGCR NPPGEDCEPL VGSPKRGPLP QCAYGMGLPP 

       490        500        510        520        530        540 
EEEASRTEAR DQPEDGADGR LPSSARAGAG SGSSPGGQSP ASGNVTGNSN STFISSGQVM 

       550        560        570        580        590        600 
NFKGDIIVVY VSQTSQEGAA AAAEPMGRPV QEETLARRDS FAGNGPRFPD PCGGPEGLRE 

       610 
PEKASRPVQE QGGAKA 

« Hide

Isoform 2 (delta7,8,9) [UniParc].

Checksum: 0EF38515CF29F18D
Show »

FASTA29932,318
Isoform 3 (delta8,9) [UniParc].

Checksum: 9200CEF495CCF5B3
Show »

FASTA33736,399
Isoform 4 (delta9) [UniParc].

Checksum: A6E72E8DEFA676C2
Show »

FASTA26328,965
Isoform 5 (exon9a) [UniParc].

Checksum: 653957CFE411BEB5
Show »

FASTA52356,402
Isoform RANK-e5a [UniParc].

Checksum: 820338A19FAE9D03
Show »

FASTA60264,552

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: Dendritic cell.
[2]"Alternative splicing generates a truncated isoform of human TNFRSF11A (RANK) with an altered capacity to activate NF-kappaB."
Sirinian C., Papanastasiou A.D., Zarkadis I.K., Kalofonos H.P.
Gene 525:124-129(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM RANK-E5A), SUBCELLULAR LOCATION (ISOFORMS 1 AND RANK-E5A), ALTERNATIVE SPLICING.
Tissue: Blood.
[3]"Alternative splicing generates multiple human TNFRSF11A (RANK) isoforms."
Papanastasiou A.D., Sirinian C., Kalofonos H.P.
Submitted (JUN-2012) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2; 3 AND 4), NUCLEOTIDE SEQUENCE [MRNA] OF 159-523 (ISOFORM 5), ALTERNATIVE SPLICING.
Tissue: Blood.
[4]"Homo sapiens protein coding cDNA."
Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S., Ohara O., Nagase T., Kikuno R.F.
Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
Tissue: Brain.
[5]"RANK is the essential signaling receptor for osteoclast differentiation factor in osteoclastogenesis."
Nakagawa N., Kinosaki M., Yamaguchi K., Shima N., Yasuda H., Yano K., Morinaga T., Higashio K.
Biochem. Biophys. Res. Commun. 253:395-400(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[6]"The TRAF family of signal transducers mediates NF-kappaB activation by the TRANCE receptor."
Wong B.R., Josien R., Lee S.Y., Vologodskaia M., Steinman R.M., Choi Y.
J. Biol. Chem. 273:28355-28359(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH TRAF1; TRAF2; TRAF3; TRAF5 AND TRAF6.
[7]"The molecular scaffold Gab2 is a crucial component of RANK signaling and osteoclastogenesis."
Wada T., Nakashima T., Oliveira-dos-Santos A.J., Gasser J., Hara H., Schett G., Penninger J.M.
Nat. Med. 11:394-399(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH GAB2.
[8]"A quantitative atlas of mitotic phosphorylation."
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[9]"Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis."
Hughes A.E., Ralston S.H., Marken J., Bell C., MacPherson H., Wallace R.G.H., van Hul W., Whyte M.P., Nakatsuka K., Hovy L., Anderson D.M.
Nat. Genet. 24:45-48(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT FEO LEU-LEU-CYS-ALA-LEU-LEU-21 INS, VARIANT PDB2 ALA-LEU-LEU-LEU-LEU-CYS-ALA-LEU-LEU-21 INS, VARIANT VAL-192.
[10]"Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations."
Guerrini M.M., Sobacchi C., Cassani B., Abinun M., Kilic S.S., Pangrazio A., Moratto D., Mazzolari E., Clayton-Smith J., Orchard P., Coxon F.P., Helfrich M.H., Crockett J.C., Mellis D., Vellodi A., Tezcan I., Notarangelo L.D., Rogers M.J. expand/collapse author list , Vezzoni P., Villa A., Frattini A.
Am. J. Hum. Genet. 83:64-76(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS OPTB7 ARG-53; CYS-129; GLY-170; ARG-175 AND SER-244.
+Additional computationally mapped references.

Web resources

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF018253 mRNA. Translation: AAB86809.1.
HF584702 mRNA. Translation: CCQ44072.1.
HE647782 mRNA. Translation: CCF23032.1.
HE649916 mRNA. Translation: CCF55033.1.
HE649917 mRNA. Translation: CCF55034.1.
HE659518 mRNA. Translation: CCF77738.1.
AB209762 mRNA. Translation: BAD92999.1. Different initiation.
RefSeqNP_001257880.1. NM_001270951.1.
NP_003830.1. NM_003839.3.
UniGeneHs.204044.
Hs.621477.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1LB5X-ray2.40B343-349[»]
ProteinModelPortalQ9Y6Q6.
SMRQ9Y6Q6. Positions 32-198.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid114320. 9 interactions.
IntActQ9Y6Q6. 4 interactions.
STRING9606.ENSP00000269485.

Chemistry

GuidetoPHARMACOLOGY1881.

PTM databases

PhosphoSiteQ9Y6Q6.

Polymorphism databases

DMDM19924309.

Proteomic databases

PaxDbQ9Y6Q6.
PRIDEQ9Y6Q6.

Protocols and materials databases

DNASU8792.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000269485; ENSP00000269485; ENSG00000141655. [Q9Y6Q6-2]
ENST00000586569; ENSP00000465500; ENSG00000141655. [Q9Y6Q6-1]
GeneID8792.
KEGGhsa:8792.
UCSCuc002lin.4. human. [Q9Y6Q6-1]

Organism-specific databases

CTD8792.
GeneCardsGC18P059992.
HGNCHGNC:11908. TNFRSF11A.
HPACAB010391.
HPA027728.
MIM174810. phenotype.
602080. phenotype.
603499. gene.
612301. phenotype.
neXtProtNX_Q9Y6Q6.
Orphanet85195. Familial expansile osteolysis.
178389. Osteopetrosis - hypogammaglobulinemia.
PharmGKBPA36601.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG45473.
HOGENOMHOG000154659.
HOVERGENHBG079274.
InParanoidQ9Y6Q6.
KOK05147.
OMACPHWAAS.
OrthoDBEOG786H2Q.
PhylomeDBQ9Y6Q6.

Enzyme and pathway databases

SignaLinkQ9Y6Q6.

Gene expression databases

ArrayExpressQ9Y6Q6.
BgeeQ9Y6Q6.
CleanExHS_TNFRSF11A.
GenevestigatorQ9Y6Q6.

Family and domain databases

InterProIPR001368. TNFR/NGFR_Cys_rich_reg.
IPR022323. TNFR_11.
IPR022361. TNFR_11A.
[Graphical view]
PfamPF00020. TNFR_c6. 1 hit.
[Graphical view]
PRINTSPR01961. TNFACTORR11.
PR01974. TNFACTORR11A.
SMARTSM00208. TNFR. 4 hits.
[Graphical view]
PROSITEPS00652. TNFR_NGFR_1. 1 hit.
PS50050. TNFR_NGFR_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GeneWikiRANK.
GenomeRNAi8792.
NextBio32972.
PROQ9Y6Q6.
SOURCESearch...

Entry information

Entry nameTNR11_HUMAN
AccessionPrimary (citable) accession number: Q9Y6Q6
Secondary accession number(s): I4EC36 expand/collapse secondary AC list , I4EC38, I4EC39, I7JE63, N0GVH0, Q59EP9
Entry history
Integrated into UniProtKB/Swiss-Prot: September 26, 2001
Last sequence update: November 1, 1999
Last modified: April 16, 2014
This is version 126 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 18

Human chromosome 18: entries, gene names and cross-references to MIM

Human cell differentiation molecules

CD nomenclature of surface proteins of human leucocytes and list of entries