ID TNR11_HUMAN Reviewed; 616 AA. AC Q9Y6Q6; I4EC39; DT 26-SEP-2001, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1999, sequence version 1. DT 22-JAN-2014, entry version 123. DE RecName: Full=Tumor necrosis factor receptor superfamily member 11A; DE AltName: Full=Osteoclast differentiation factor receptor; DE Short=ODFR; DE AltName: Full=Receptor activator of NF-KB; DE AltName: CD_antigen=CD265; DE Flags: Precursor; GN Name=TNFRSF11A; Synonyms=RANK; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Dendritic cell; RX PubMed=9367155; DOI=10.1038/36593; RA Anderson D.M., Maraskovsky E., Billingsley W.L., Dougall W.C., RA Tometsko M.E., Roux E.R., Teepe M.C., DuBose R.F., Cosman D., RA Galibert L.; RT "A homologue of the TNF receptor and its ligand enhance T-cell growth RT and dendritic-cell function."; RL Nature 390:175-179(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND ALTERNATIVE SPLICING. RC TISSUE=Blood; RA Papanastasiou A.D., Sirinian C., Kalofonos H.P.; RT "Alternative splicing generates multiple human TNFRSF11A (RANK) RT isoforms."; RL Submitted (JUN-2012) to the EMBL/GenBank/DDBJ databases. RN [3] RP FUNCTION. RX PubMed=9878548; DOI=10.1006/bbrc.1998.9788; RA Nakagawa N., Kinosaki M., Yamaguchi K., Shima N., Yasuda H., Yano K., RA Morinaga T., Higashio K.; RT "RANK is the essential signaling receptor for osteoclast RT differentiation factor in osteoclastogenesis."; RL Biochem. Biophys. Res. Commun. 253:395-400(1998). RN [4] RP INTERACTION WITH TRAF1; TRAF2; TRAF3; TRAF5 AND TRAF6. RX PubMed=9774460; DOI=10.1074/jbc.273.43.28355; RA Wong B.R., Josien R., Lee S.Y., Vologodskaia M., Steinman R.M., RA Choi Y.; RT "The TRAF family of signal transducers mediates NF-kappaB activation RT by the TRANCE receptor."; RL J. Biol. Chem. 273:28355-28359(1998). RN [5] RP INTERACTION WITH GAB2. RX PubMed=15750601; DOI=10.1038/nm1203; RA Wada T., Nakashima T., Oliveira-dos-Santos A.J., Gasser J., Hara H., RA Schett G., Penninger J.M.; RT "The molecular scaffold Gab2 is a crucial component of RANK signaling RT and osteoclastogenesis."; RL Nat. Med. 11:394-399(2005). RN [6] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [7] RP VARIANT FEO LEU-LEU-CYS-ALA-LEU-LEU-21 INS, VARIANT PDB2 RP ALA-LEU-LEU-LEU-LEU-CYS-ALA-LEU-LEU-21 INS, AND VARIANT VAL-192. RX PubMed=10615125; DOI=10.1038/71667; RA Hughes A.E., Ralston S.H., Marken J., Bell C., MacPherson H., RA Wallace R.G.H., van Hul W., Whyte M.P., Nakatsuka K., Hovy L., RA Anderson D.M.; RT "Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause RT familial expansile osteolysis."; RL Nat. Genet. 24:45-48(2000). RN [8] RP VARIANTS OPTB7 ARG-53; CYS-129; GLY-170; ARG-175 AND SER-244. RX PubMed=18606301; DOI=10.1016/j.ajhg.2008.06.015; RA Guerrini M.M., Sobacchi C., Cassani B., Abinun M., Kilic S.S., RA Pangrazio A., Moratto D., Mazzolari E., Clayton-Smith J., Orchard P., RA Coxon F.P., Helfrich M.H., Crockett J.C., Mellis D., Vellodi A., RA Tezcan I., Notarangelo L.D., Rogers M.J., Vezzoni P., Villa A., RA Frattini A.; RT "Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to RT TNFRSF11A (RANK) mutations."; RL Am. J. Hum. Genet. 83:64-76(2008). CC -!- FUNCTION: Receptor for TNFSF11/RANKL/TRANCE/OPGL; essential for CC RANKL-mediated osteoclastogenesis. Involved in the regulation of CC interactions between T-cells and dendritic cells. CC -!- SUBUNIT: Binds to the clefts between the subunits of the TNFSF11 CC ligand trimer to form a heterohexamer (By similarity). Interacts CC with TRAF1, TRAF2, TRAF3, TRAF5 and TRAF6. Interacts (via CC cytoplasmic domain) with GAB2. CC -!- SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane CC protein (Potential). CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q9Y6Q6-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9Y6Q6-2; Sequence=VSP_046901; CC Note=No experimental confirmation available; CC -!- TISSUE SPECIFICITY: Ubiquitous expression with high levels in CC skeletal muscle, thymus, liver, colon, small intestine and adrenal CC gland. CC -!- DISEASE: Familial expansile osteolysis (FEO) [MIM:174810]: Rare CC autosomal dominant bone disorder characterized by focal areas of CC increased bone remodeling. The osteolytic lesions develop usually CC in the long bones during early adulthood. FEO is often associated CC with early-onset deafness and loss of dentition. Note=The disease CC is caused by mutations affecting the gene represented in this CC entry. CC -!- DISEASE: Paget disease of bone 2 (PDB2) [MIM:602080]: Bone- CC remodeling disorder with clinical similarities to FEO. Unlike FEO, CC however, affected individuals have involvement of the axial CC skeleton with lesions in the spine, pelvis and skull. Note=The CC disease is caused by mutations affecting the gene represented in CC this entry. CC -!- DISEASE: Osteopetrosis, autosomal recessive 7 (OPTB7) CC [MIM:612301]: A rare genetic disease characterized by abnormally CC dense bone, due to defective resorption of immature bone. CC Osteopetrosis occurs in two forms: a severe autosomal recessive CC form occurring in utero, infancy, or childhood, and a benign CC autosomal dominant form occurring in adolescence or adulthood. CC Recessive osteopetrosis commonly manifests in early infancy with CC macrocephaly, feeding difficulties, evolving blindness and CC deafness, bone marrow failure, severe anemia, and CC hepatosplenomegaly. Deafness and blindness are generally thought CC to represent effects of pressure on nerves. OPTB7 is characterized CC by paucity of osteoclasts, suggesting a molecular defect in CC osteoclast development. OPTB7 is associated with CC hypogammaglobulinemia. Note=The disease is caused by mutations CC affecting the gene represented in this entry. CC -!- SIMILARITY: Contains 4 TNFR-Cys repeats. CC -!- WEB RESOURCE: Name=GeneReviews; CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/TNFRSF11A"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF018253; AAB86809.1; -; mRNA. DR EMBL; HE649917; CCF55034.1; -; mRNA. DR RefSeq; NP_001257880.1; NM_001270951.1. DR RefSeq; NP_003830.1; NM_003839.3. DR UniGene; Hs.204044; -. DR UniGene; Hs.621477; -. DR PDB; 1LB5; X-ray; 2.40 A; B=343-349. DR PDBsum; 1LB5; -. DR ProteinModelPortal; Q9Y6Q6; -. DR SMR; Q9Y6Q6; 32-198. DR IntAct; Q9Y6Q6; 4. DR STRING; 9606.ENSP00000269485; -. DR GuidetoPHARMACOLOGY; 1881; -. DR PhosphoSite; Q9Y6Q6; -. DR DMDM; 19924309; -. DR PaxDb; Q9Y6Q6; -. DR PRIDE; Q9Y6Q6; -. DR DNASU; 8792; -. DR Ensembl; ENST00000269485; ENSP00000269485; ENSG00000141655. DR Ensembl; ENST00000586569; ENSP00000465500; ENSG00000141655. DR GeneID; 8792; -. DR KEGG; hsa:8792; -. DR UCSC; uc010dpv.4; human. DR CTD; 8792; -. DR GeneCards; GC18P059992; -. DR HGNC; HGNC:11908; TNFRSF11A. DR HPA; CAB010391; -. DR HPA; HPA027728; -. DR MIM; 174810; phenotype. DR MIM; 602080; phenotype. DR MIM; 603499; gene. DR MIM; 612301; phenotype. DR neXtProt; NX_Q9Y6Q6; -. DR Orphanet; 667; Autosomal recessive malignant osteopetrosis. DR Orphanet; 85195; Familial expansile osteolysis. DR Orphanet; 178389; Osteopetrosis - hypogammaglobulinemia. DR PharmGKB; PA36601; -. DR eggNOG; NOG45473; -. DR HOGENOM; HOG000154659; -. DR HOVERGEN; HBG079274; -. DR InParanoid; Q9Y6Q6; -. DR KO; K05147; -. DR OMA; CPHWAAS; -. DR OrthoDB; EOG786H2Q; -. DR PhylomeDB; Q9Y6Q6; -. DR SignaLink; Q9Y6Q6; -. DR GeneWiki; RANK; -. DR GenomeRNAi; 8792; -. DR NextBio; 32972; -. DR PRO; PR:Q9Y6Q6; -. DR ArrayExpress; Q9Y6Q6; -. DR Bgee; Q9Y6Q6; -. DR CleanEx; HS_TNFRSF11A; -. DR Genevestigator; Q9Y6Q6; -. DR GO; GO:0009897; C:external side of plasma membrane; IDA:BHF-UCL. DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0005031; F:tumor necrosis factor-activated receptor activity; ISS:BHF-UCL. DR GO; GO:0002250; P:adaptive immune response; IMP:BHF-UCL. DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc. DR GO; GO:0060086; P:circadian temperature homeostasis; ISS:BHF-UCL. DR GO; GO:0048535; P:lymph node development; IEA:Ensembl. DR GO; GO:0060749; P:mammary gland alveolus development; IEA:Ensembl. DR GO; GO:0002548; P:monocyte chemotaxis; NAS:BHF-UCL. DR GO; GO:0001503; P:ossification; IEA:Ensembl. DR GO; GO:0030316; P:osteoclast differentiation; IMP:BHF-UCL. DR GO; GO:0008284; P:positive regulation of cell proliferation; TAS:ProtInc. DR GO; GO:0071848; P:positive regulation of ERK1 and ERK2 cascade via TNFSF11-mediated signaling; IMP:BHF-UCL. DR GO; GO:0071812; P:positive regulation of fever generation by positive regulation of prostaglandin secretion; ISS:BHF-UCL. DR GO; GO:0043507; P:positive regulation of JUN kinase activity; IMP:BHF-UCL. DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IDA:BHF-UCL. DR GO; GO:0070555; P:response to interleukin-1; ISS:BHF-UCL. DR GO; GO:0032496; P:response to lipopolysaccharide; ISS:BHF-UCL. DR GO; GO:0009314; P:response to radiation; IEA:Ensembl. DR InterPro; IPR001368; TNFR/NGFR_Cys_rich_reg. DR InterPro; IPR022323; TNFR_11. DR InterPro; IPR022361; TNFR_11A. DR Pfam; PF00020; TNFR_c6; 1. DR PRINTS; PR01961; TNFACTORR11. DR PRINTS; PR01974; TNFACTORR11A. DR SMART; SM00208; TNFR; 4. DR PROSITE; PS00652; TNFR_NGFR_1; 1. DR PROSITE; PS50050; TNFR_NGFR_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Complete proteome; Deafness; KW Disease mutation; Disulfide bond; Glycoprotein; Membrane; KW Metal-binding; Osteopetrosis; Polymorphism; Receptor; KW Reference proteome; Repeat; Signal; Sodium; Transmembrane; KW Transmembrane helix. FT SIGNAL 1 29 Potential. FT CHAIN 30 616 Tumor necrosis factor receptor FT superfamily member 11A. FT /FTId=PRO_0000034585. FT TOPO_DOM 30 212 Extracellular (Potential). FT TRANSMEM 213 233 Helical; (Potential). FT TOPO_DOM 234 616 Cytoplasmic (Potential). FT REPEAT 34 68 TNFR-Cys 1. FT REPEAT 71 112 TNFR-Cys 2. FT REPEAT 114 151 TNFR-Cys 3. FT REPEAT 154 194 TNFR-Cys 4. FT METAL 133 133 Sodium; via carbonyl oxygen (By FT similarity). FT METAL 134 134 Sodium; via carbonyl oxygen (By FT similarity). FT METAL 160 160 Sodium; via carbonyl oxygen (By FT similarity). FT CARBOHYD 105 105 N-linked (GlcNAc...) (Potential). FT CARBOHYD 174 174 N-linked (GlcNAc...) (Potential). FT DISULFID 34 46 By similarity. FT DISULFID 47 60 By similarity. FT DISULFID 50 68 By similarity. FT DISULFID 71 86 By similarity. FT DISULFID 92 112 By similarity. FT DISULFID 114 127 By similarity. FT DISULFID 124 126 By similarity. FT DISULFID 133 151 By similarity. FT DISULFID 154 169 By similarity. FT DISULFID 175 194 By similarity. FT VAR_SEQ 206 522 Missing (in isoform 2). FT /FTId=VSP_046901. FT VARIANT 21 21 L -> LALLLLCALL (in PDB2). FT /FTId=VAR_011516. FT VARIANT 21 21 L -> LLLCALL (in FEO). FT /FTId=VAR_011517. FT VARIANT 53 53 G -> R (in OPTB7; two patients with FT osteoclast-poor osteopetrosis). FT /FTId=VAR_046788. FT VARIANT 129 129 R -> C (in OPTB7; a patient with FT osteoclast-poor osteopetrosis). FT /FTId=VAR_046789. FT VARIANT 141 141 H -> Y (in dbSNP:rs35211496). FT /FTId=VAR_046790. FT VARIANT 170 170 R -> G (in OPTB7; two siblings with FT osteoclast-poor osteopetrosis). FT /FTId=VAR_046791. FT VARIANT 175 175 C -> R (in OPTB7; two patients with FT osteoclast-poor osteopetrosis). FT /FTId=VAR_046792. FT VARIANT 192 192 A -> V (in dbSNP:rs1805034). FT /FTId=VAR_011518. FT VARIANT 244 244 A -> S (in OPTB7; one patient with FT osteoclast-poor osteopetrosis). FT /FTId=VAR_046793. FT STRAND 345 348 SQ SEQUENCE 616 AA; 66034 MW; E3DE9A7A08196F81 CRC64; MAPRARRRRP LFALLLLCAL LARLQVALQI APPCTSEKHY EHLGRCCNKC EPGKYMSSKC TTTSDSVCLP CGPDEYLDSW NEEDKCLLHK VCDTGKALVA VVAGNSTTPR RCACTAGYHW SQDCECCRRN TECAPGLGAQ HPLQLNKDTV CKPCLAGYFS DAFSSTDKCR PWTNCTFLGK RVEHHGTEKS DAVCSSSLPA RKPPNEPHVY LPGLIILLLF ASVALVAAII FGVCYRKKGK ALTANLWHWI NEACGRLSGD KESSGDSCVS THTANFGQQG ACEGVLLLTL EEKTFPEDMC YPDQGGVCQG TCVGGGPYAQ GEDARMLSLV SKTEIEEDSF RQMPTEDEYM DRPSQPTDQL LFLTEPGSKS TPPFSEPLEV GENDSLSQCF TGTQSTVGSE SCNCTEPLCR TDWTPMSSEN YLQKEVDSGH CPHWAASPSP NWADVCTGCR NPPGEDCEPL VGSPKRGPLP QCAYGMGLPP EEEASRTEAR DQPEDGADGR LPSSARAGAG SGSSPGGQSP ASGNVTGNSN STFISSGQVM NFKGDIIVVY VSQTSQEGAA AAAEPMGRPV QEETLARRDS FAGNGPRFPD PCGGPEGLRE PEKASRPVQE QGGAKA //