Q9Y6Q6 (TNR11_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	616 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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.2
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.3 Ref.4
Subcellular location	Membrane; Single-pass type I membrane protein Potential.
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.6 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.6 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. 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.7
Sequence similarities	Contains 4 TNFR-Cys repeats.

Ontologies

Keywords
Cellular component	Membrane
Coding sequence diversity	Polymorphism
Disease	Deafness Disease mutation Osteopetrosis
Domain	Repeat Signal Transmembrane Transmembrane helix
Ligand	Metal-binding Sodium
Molecular function	Receptor
PTM	Disulfide bond Glycoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	adaptive immune response Inferred from mutant phenotype Ref.7. 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 monocyte chemotaxis Non-traceable author statement PubMed 15248232. Source: BHF-UCL osteoclast differentiation Inferred from mutant phenotype Ref.7. Source: BHF-UCL positive regulation of ERK1 and ERK2 cascade via TNFSF11-mediated signaling Inferred from mutant phenotype Ref.7. 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 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
Cellular_component	external side of plasma membrane Inferred from direct assay Ref.1. Source: BHF-UCL integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW
Molecular_function	metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW tumor necrosis factor-activated receptor activity Inferred from sequence or structural similarity PubMed 19940926. Source: BHF-UCL
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 29	29	Potential
	Chain	30 – 616	587	Tumor necrosis factor receptor superfamily member 11A		PRO_0000034585
Regions
	Topological domain	30 – 212	183	Extracellular Potential
	Transmembrane	213 – 233	21	Helical; Potential
	Topological domain	234 – 616	383	Cytoplasmic Potential
	Repeat	34 – 68	35	TNFR-Cys 1
	Repeat	71 – 112	42	TNFR-Cys 2
	Repeat	114 – 151	38	TNFR-Cys 3
	Repeat	154 – 194	41	TNFR-Cys 4
Sites
	Metal binding	133	1	Sodium; via carbonyl oxygen By similarity
	Metal binding	134	1	Sodium; via carbonyl oxygen By similarity
	Metal binding	160	1	Sodium; via carbonyl oxygen By similarity
Amino acid modifications
	Glycosylation	105	1	N-linked (GlcNAc...) Potential
	Glycosylation	174	1	N-linked (GlcNAc...) Potential
	Disulfide bond	34 ↔ 46		By similarity
	Disulfide bond	47 ↔ 60		By similarity
	Disulfide bond	50 ↔ 68		By similarity
	Disulfide bond	71 ↔ 86		By similarity
	Disulfide bond	92 ↔ 112		By similarity
	Disulfide bond	114 ↔ 127		By similarity
	Disulfide bond	124 ↔ 126		By similarity
	Disulfide bond	133 ↔ 151		By similarity
	Disulfide bond	154 ↔ 169		By similarity
	Disulfide bond	175 ↔ 194		By similarity
Natural variations
	Natural variant	21	1	L → LALLLLCALL in PDB2.		VAR_011516
	Natural variant	21	1	L → LLLCALL in FEO. Ref.6		VAR_011517
	Natural variant	53	1	G → R in OPTB7; two patients with osteoclast-poor osteopetrosis. Ref.7		VAR_046788
	Natural variant	129	1	R → C in OPTB7; a patient with osteoclast-poor osteopetrosis. Ref.7		VAR_046789
	Natural variant	141	1	H → Y. Corresponds to variant rs35211496 [ dbSNP | Ensembl ].		VAR_046790
	Natural variant	170	1	R → G in OPTB7; two siblings with osteoclast-poor osteopetrosis. Ref.7		VAR_046791
	Natural variant	175	1	C → R in OPTB7; two patients with osteoclast-poor osteopetrosis. Ref.7		VAR_046792
	Natural variant	192	1	A → V. Ref.6 Corresponds to variant rs1805034 [ dbSNP | Ensembl ].		VAR_011518
	Natural variant	244	1	A → S in OPTB7; one patient with osteoclast-poor osteopetrosis. Ref.7		VAR_046793

Sequences

	Sequence		Length	Mass (Da)
	Q9Y6Q6 [UniParc]. Last modified November 1, 1999. Version 1. Checksum: E3DE9A7A08196F81	FASTA	616	66,034
	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

References

	« Hide 'large scale' referencesShow '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]. Tissue: Dendritic cell.
[2]	"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.
[3]	"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.
[4]	"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.
[5]	"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.
[6]	"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.
[7]	"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. , 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

GeneReviews

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF018253 mRNA. Translation: AAB86809.1.
IPI	IPI00021968.
RefSeq	NP_003830.1. NM_003839.3.
UniGene	Hs.204044. Hs.621477.
3D structure databases
ProteinModelPortal	Q9Y6Q6.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q9Y6Q6. 3 interactions.
STRING	9606.ENSP00000269485.
PTM databases
PhosphoSite	Q9Y6Q6.
Polymorphism databases
DMDM	19924309.
Proteomic databases
PaxDb	Q9Y6Q6.
PRIDE	Q9Y6Q6.
Protocols and materials databases
DNASU	8792.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000586569; ENSP00000465500; ENSG00000141655.
GeneID	8792.
KEGG	hsa:8792.
UCSC	uc002lin.3. human.
Organism-specific databases
CTD	8792.
GeneCards	GC18P059992.
HGNC	HGNC:11908. TNFRSF11A.
HPA	CAB010391. HPA027728.
MIM	174810. phenotype. 602080. phenotype. 603499. gene. 612301. phenotype.
neXtProt	NX_Q9Y6Q6.
Orphanet	667. Autosomal recessive malignant osteopetrosis. 85195. Familial expansile osteolysis. 178389. Osteopetrosis - hypogammaglobulinemia.
PharmGKB	PA36601.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG45473.
HOGENOM	HOG000154659.
HOVERGEN	HBG079274.
InParanoid	Q9Y6Q6.
KO	K05147.
OMA	CPHWAAS.
OrthoDB	EOG42V8FV.
PhylomeDB	Q9Y6Q6.
Gene expression databases
ArrayExpress	Q9Y6Q6.
Bgee	Q9Y6Q6.
CleanEx	HS_TNFRSF11A.
Genevestigator	Q9Y6Q6.
GermOnline	ENSG00000141655. Homo sapiens.
Family and domain databases
InterPro	IPR001368. TNFR/NGFR_Cys_rich_reg. IPR022323. TNFR_11. IPR022361. TNFR_11A. [Graphical view]
Pfam	PF00020. TNFR_c6. 1 hit. [Graphical view]
PRINTS	PR01961. TNFACTORR11. PR01974. TNFACTORR11A.
SMART	SM00208. TNFR. 4 hits. [Graphical view]
PROSITE	PS00652. TNFR_NGFR_1. 1 hit. PS50050. TNFR_NGFR_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other
GenomeRNAi	8792.
NextBio	32972.
SOURCE	Search...

Entry information

Entry name

TNR11_HUMAN

Accession

Primary (citable) accession number: Q9Y6Q6

Entry history

Integrated into UniProtKB/Swiss-Prot:	September 26, 2001
Last sequence update:	November 1, 1999
Last modified:	May 1, 2013
This is version 115 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.