Reviewed, UniProtKB/Swiss-Prot O00300 (TR11B_HUMAN)

Names and origin

Protein names

Recommended name:
    Tumor necrosis factor receptor superfamily member 11B
Alternative name(s):
    Osteoprotegerin
    Osteoclastogenesis inhibitory factor

Gene names

Name:	TNFRSF11B
Synonyms:	OCIF, OPG

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	401 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	Acts as decoy receptor for RANKL and thereby neutralizes its function in osteoclastogenesis. Inhibits the activation of osteoclasts and promotes osteoclast apoptosis in vitro. Bone homeostasis seems to depend on the local RANKL/OPG ratio. May also play a role in preventing arterial calcification. May act as decoy receptor for TRAIL and protect against apoptosis. TRAIL binding blocks the inhibition of osteoclastogenesis. Ref.11
Subunit structure	Homodimer.
Subcellular location	Secreted.
Tissue specificity	Highly expressed in adult lung, heart, kidney, liver, spleen, thymus, prostate, ovary, small intestine, thyroid, lymph node, trachea, adrenal gland, testis, and bone marrow. Detected at very low levels in brain, placenta and skeletal muscle. Highly expressed in fetal kidney, liver and lung.
Induction	Up-regulated by increasing calcium-concentration in the medium and estrogens. Down-regulated by glucocorticoids.
Post-translational modification	N-glycosylated. Contains sialic acid residues. The N-terminus is blocked.
Involvement in disease	Defects in TNFRSF11B are the cause of juvenile Paget disease (JPD) [MIM:239000]; also called hyperostosis corticalis deformans juvenilis or hereditary hyperphosphatasia or chronic congenital idiopathic hyperphosphatasia. JPD is a rare autosomal recessive osteopathy that presents in infancy or early childhood. The disorder is characterized by rapidly remodeling woven bone, osteopenia, debilitating fractures, and deformities due to a markedly accelerated rate of bone remodeling throughout the skeleton. Approximately 40 cases of JPD have been reported worldwide. Unless it is treated with drugs that block osteoclast-mediated skeletal resorption, the disease can be fatal. Ref.15
Sequence similarities	Contains 2 death domains. Contains 4 TNFR-Cys repeats.

Ontologies

Keywords
Biological process	Apoptosis
Cellular component	Secreted
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Domain	Repeat Signal
Molecular function	Receptor
PTM	Disulfide bond Glycoprotein
Technical term	Direct protein sequencing
Gene Ontology (GO)
Biological process	apoptosis Inferred from electronic annotation. Source: UniProtKB-KW signal transduction Ref.11 Traceable author statement. Source: ProtInc skeletal system development Ref.1 Traceable author statement. Source: ProtInc
Molecular function	cytokine activity Ref.11 Traceable author statement. Source: ProtInc receptor activity Ref.1 Traceable author statement. Source: ProtInc
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 21	21	Ref.8 Ref.9
	Chain	22 – 401	380	Tumor necrosis factor receptor superfamily member 11B		PRO_0000034587
Regions
	Repeat	24 – 62	39	TNFR-Cys 1
	Repeat	65 – 105	41	TNFR-Cys 2
	Repeat	107 – 142	36	TNFR-Cys 3
	Repeat	145 – 185	41	TNFR-Cys 4
	Domain	198 – 269	72	Death 1
	Domain	270 – 365	96	Death 2
Sites
	Site	400	1	Involved in dimerization
Amino acid modifications
	Glycosylation	98	1	N-linked (GlcNAc...) Potential
	Glycosylation	152	1	N-linked (GlcNAc...) Potential
	Glycosylation	165	1	N-linked (GlcNAc...) Potential
	Glycosylation	178	1	N-linked (GlcNAc...) Potential
	Glycosylation	289	1	N-linked (GlcNAc...) Potential
	Disulfide bond	41 ↔ 54		By similarity
	Disulfide bond	44 ↔ 62		By similarity
	Disulfide bond	65 ↔ 80		By similarity
	Disulfide bond	83 ↔ 97		By similarity
	Disulfide bond	87 ↔ 105		By similarity
	Disulfide bond	107 ↔ 118		By similarity
	Disulfide bond	124 ↔ 142		By similarity
	Disulfide bond	145 ↔ 160		By similarity
	Disulfide bond	166 ↔ 185		By similarity
Natural variations
	Natural variant	3	1	K → N: dbSNP rs2073618. Ref.3 Ref.5 Ref.6 Ref.7		VAR_013439
	Natural variant	104	1	V → M: dbSNP rs11573906. Ref.6		VAR_018957
	Natural variant	182	1	Missing in JPD. Ref.15		VAR_019413
Experimental info
	Mutagenesis	400 – 401	2	Missing: Abolishes dimerization. Ref.13
	Mutagenesis	400	1	C → S: Abolishes dimerization. Ref.13
	Sequence conflict	263	1	D → A in AAB53709. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	O00300-1 [UniParc]. Last modified May 27, 2002. Version 2. Checksum: EDF448B67D86C71E	FASTA	401	46,040
	10 20 30 40 50 60 MNKLLCCALV FLDISIKWTT QETFPPKYLH YDEETSHQLL CDKCPPGTYL KQHCTAKWKT 70 80 90 100 110 120 VCAPCPDHYY TDSWHTSDEC LYCSPVCKEL QYVKQECNRT HNRVCECKEG RYLEIEFCLK 130 140 150 160 170 180 HRSCPPGFGV VQAGTPERNT VCKRCPDGFF SNETSSKAPC RKHTNCSVFG LLLTQKGNAT 190 200 210 220 230 240 HDNICSGNSE STQKCGIDVT LCEEAFFRFA VPTKFTPNWL SVLVDNLPGT KVNAESVERI 250 260 270 280 290 300 KRQHSSQEQT FQLLKLWKHQ NKDQDIVKKI IQDIDLCENS VQRHIGHANL TFEQLRSLME 310 320 330 340 350 360 SLPGKKVGAE DIEKTIKACK PSDQILKLLS LWRIKNGDQD TLKGLMHALK HSKTYHFPKT 370 380 390 400 VTQSLKKTIR FLHSFTMYKL YQKLFLEMIG NQVQSVKISC L

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Osteoprotegerin: a novel secreted protein involved in the regulation of bone density." Simonet W.S., Lacey D.L., Dunstan C.R., Kelley M., Chang M.-S., Luethy R., Nguyen H.Q., Wooden S., Bennett L., Boone T., Shimamoto G., Derose M., Elliott R., Colombero A., Tan H.-L., Trail G., Sullivan J., Davy E. , Bucay N., Renshaw-Gegg L., Hughes T.M., Hill D., Pattison W., Campbell P., Sander S., Van G., Tarpley J., Derby P., Lee R., Suggs S., Boyle W.J. Cell 89:309-319(1997) [PubMed: 9108485] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Kidney.
[2]	"Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro." Yasuda H., Shima N., Nakagawa N., Mochizuki S., Yano K., Fujise N., Sato Y., Goto M., Yamaguchi K., Kuriyama M., Kanno T., Murakami A., Tsuda E., Morinaga T., Higashio K. Endocrinology 139:1329-1337(1998) [PubMed: 9492069] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Lung cancer.
[3]	"Cloning and characterization of the gene encoding human osteoprotegerin/osteoclastogenesis-inhibitory factor." Morinaga T., Nakagawa N., Yasuda H., Tsuda E., Higashio K. Eur. J. Biochem. 254:685-691(1998) [PubMed: 9688283] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT ASN-3. Tissue: Placenta.
[4]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Kidney.
[5]	Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S. Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT ASN-3. Tissue: Lung.
[6]	NIEHS SNPs program Submitted (NOV-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS ASN-3 AND MET-104.
[7]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT ASN-3. Tissue: Eye.
[8]	"Characterization of monomeric and homodimeric forms of osteoclastogenesis inhibitory factor." Tomoyasu A., Goto M., Fujise N., Mochizuki S., Yasuda H., Morinaga T., Tsuda E., Higashio K. Biochem. Biophys. Res. Commun. 245:382-387(1998) [PubMed: 9571159] [Abstract] Cited for: PROTEIN SEQUENCE OF 22-36 AND 378-401.
[9]	"Signal peptide prediction based on analysis of experimentally verified cleavage sites." Zhang Z., Henzel W.J. Protein Sci. 13:2819-2824(2004) [PubMed: 15340161] [Abstract] Cited for: PROTEIN SEQUENCE OF 22-36.
[10]	"Cloning and expression of osteoprotegerin from Homo sapiens." He Z.-Y., Yang G.-Z., Zhang W.-J., Wu X.-F. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao 31:680-684(1999) [PubMed: 12110935] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 22-393. Tissue: Placenta.
[11]	"Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis." Tsuda E., Goto M., Mochizuki S., Yano K., Kobayashi F., Morinaga T., Higashio K. Biochem. Biophys. Res. Commun. 234:137-142(1997) [PubMed: 9168977] [Abstract] Cited for: PROTEIN SEQUENCE OF 242-255; 354-359 AND 369-378, FUNCTION.
[12]	"Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL." Emery J.G., McDonnell P., Burke M.B., Deen K.C., Lyn S., Silverman C., Dul E., Appelbaum E.R., Eichman C., DiPrinzio R., Dodds R.A., James I.E., Rosenberg M., Lee J.C., Young P.R. J. Biol. Chem. 273:14363-14367(1998) [PubMed: 9603945] [Abstract] Cited for: INTERACTION WITH TRAIL.
[13]	"Characterization of structural domains of human osteoclastogenesis inhibitory factor." Yamaguchi K., Kinosaki M., Goto M., Kobayashi F., Tsuda E., Morinaga T., Higashio K. J. Biol. Chem. 273:5117-5123(1998) [PubMed: 9478964] [Abstract] Cited for: CHARACTERIZATION, MUTAGENESIS OF CYS-400.
[14]	"Receptor activator of nuclear factor-kappaB ligand and osteoprotegerin: potential implications for the pathogenesis and treatment of malignant bone diseases." Hofbauer L.C., Neubauer A., Heufelder A.E. Cancer 92:460-470(2001) [PubMed: 11505389] [Abstract] Cited for: REVIEW.
[15]	"A mutation in the gene TNFRSF11B encoding osteoprotegerin causes an idiopathic hyperphosphatasia phenotype." Cundy T., Hegde M., Naot D., Chong B., King A., Wallace R., Mulley J., Love D.R., Seidel J., Fawkner M., Banovic T., Callon K.E., Grey A.B., Reid I.R., Middleton-Hardie C.A., Cornish J. Hum. Mol. Genet. 11:2119-2127(2002) [PubMed: 12189164] [Abstract] Cited for: VARIANT JPD ASP-182 DEL.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

NIEHS-SNPs

Cross-references

Sequence databases
EMBLGenBankDDBJ	U94332 mRNA. Translation: AAB53709.1. AB002146 mRNA. Translation: BAA25910.1. AB008822 Genomic DNA. Translation: BAA32076.1. AK313710 mRNA. Translation: BAG36455.1. AK223155 mRNA. Translation: BAD96875.1. AY466112 Genomic DNA. Translation: AAR23265.1. BC030155 mRNA. Translation: AAH30155.1. AF134187 mRNA. Translation: AAF20168.1.
IPI	IPI00298362.
RefSeq	NP_002537.3.
UniGene	Hs.81791
3D structure databases
HSSP	HSSP built from PDB template 1D0G based on UniProtKB O14763.
ModBase	Search...
Proteomic databases
PRIDE	O00300.
Genome annotation databases
Ensembl	ENSG00000164761. Homo sapiens. [Contig view]
GeneID	4982.
KEGG	hsa:4982.
Organism-specific databases
GeneCards	GC08M120004.
H-InvDB	HIX0007748.
HGNC	HGNC:11909. TNFRSF11B.
MIM	239000. phenotype. 602643. gene.
Orphanet	2801. Paget disease juvenile type.
PharmGKB	PA36602.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	O00300.
HOVERGEN	O00300.
Gene expression databases
ArrayExpress	O00300.
Bgee	O00300.
CleanEx	HS_TNFRSF11B.
GermOnline	ENSG00000164761. Homo sapiens.
Family and domain databases
InterPro	IPR000488. Death. IPR017371. TNFR_11B. IPR001368. TNFR_Cys_rich_reg. [Graphical view]
Pfam	PF00531. Death. 1 hit. PF00020. TNFR_c6. 3 hits. [Graphical view]
PIRSF	PIRSF038065. TNFR_11B. 1 hit.
SMART	SM00208. TNFR. 4 hits. [Graphical view]
PROSITE	PS50017. DEATH_DOMAIN. False negative. PS00652. TNFR_NGFR_1. 1 hit. PS50050. TNFR_NGFR_2. 2 hits. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	19182.
SOURCE	Search...

Entry information

Entry name

TR11B_HUMAN

Accession

Primary (citable) accession number: O00300
Secondary accession number(s): B2R9A8 , O60236, Q53FX6, Q9UHP4

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 27, 2002
Last sequence update:	May 27, 2002
Last modified:	May 5, 2009
This is version 84 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)