O00300 (TR11B_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Tumor necrosis factor receptor superfamily member 11B

Alternative name(s):
Osteoclastogenesis inhibitory factor
Osteoprotegerin

Gene names

Name:	TNFRSF11B
Synonyms:	OCIF, OPG

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	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 TNFSF11/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 ratio between TNFSF11 and TNFRSF11B. May also play a role in preventing arterial calcification. May act as decoy receptor for TNFSF10/TRAIL and protect against apoptosis. TNFSF10/TRAIL binding blocks the inhibition of osteoclastogenesis. Ref.12 Ref.16
Subunit structure	Homodimer. Interacts with TNFSF10 and TNFSF11. Ref.13 Ref.16
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. Ref.16 The N-terminus is blocked.
Involvement in disease	Juvenile Paget disease (JPD) [MIM:239000]: 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. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.17
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	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW extracellular matrix organization Inferred from electronic annotation. Source: Compara negative regulation of bone resorption Inferred from electronic annotation. Source: Compara negative regulation of odontogenesis of dentin-containing tooth Inferred from electronic annotation. Source: Compara response to arsenic-containing substance Inferred from electronic annotation. Source: Compara response to drug Inferred from electronic annotation. Source: Compara response to estrogen stimulus Inferred from electronic annotation. Source: Compara response to magnesium ion Inferred from electronic annotation. Source: Compara response to nutrient Inferred from electronic annotation. Source: Compara signal transduction Traceable author statement Ref.12. Source: ProtInc skeletal system development Traceable author statement Ref.1. Source: ProtInc
Cellular_component	extracellular space Inferred from direct assay PubMed 15516325. Source: BHF-UCL proteinaceous extracellular matrix Inferred from electronic annotation. Source: Compara
Molecular_function	cytokine activity Traceable author statement Ref.12. Source: ProtInc receptor activity Traceable author statement Ref.1. 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.9 Ref.10

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...) Ref.16

Glycosylation

289

1

N-linked (GlcNAc...) Potential

Disulfide bond

41 ↔ 54

Ref.16

Disulfide bond

44 ↔ 62

Ref.16

Disulfide bond

65 ↔ 80

Ref.16

Disulfide bond

83 ↔ 97

Ref.16

Disulfide bond

87 ↔ 105

Ref.16

Disulfide bond

107 ↔ 118

Ref.16

Disulfide bond

124 ↔ 142

Ref.16

Disulfide bond

145 ↔ 160

Ref.16

Disulfide bond

166 ↔ 185

Ref.16

Natural variations

Natural variant

3

1

N → K. Ref.1 Ref.2 Ref.3 Ref.4 Ref.6
Corresponds to variant rs2073618 [ dbSNP | Ensembl ].

VAR_013439

Natural variant

104

1

V → M. Ref.6
Corresponds to variant rs11573906 [ dbSNP | Ensembl ].

VAR_018957

Natural variant

182

1

Missing in JPD. Ref.17

VAR_019413

Experimental info

Mutagenesis

78 – 79

2

DE → AA: Decreases inhibition of osteoclast differentiation.

Mutagenesis

116

1

E → A: Reduces affinity for TNFSF11. Decreases inhibition of osteoclast differentiation. Ref.16

Mutagenesis

400 – 401

2

Missing: Abolishes dimerization. Ref.14

Mutagenesis

400

1

C → S: Abolishes dimerization. Ref.14

Sequence conflict

263

1

D → A in AAB53709. Ref.1

Secondary structure

1

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401

Helix Strand Turn

Details...

Beta strand

29 – 31

3

Beta strand

35 – 37

3

Beta strand

40 – 42

3

Beta strand

48 – 52

5

Beta strand

56 – 58

3

Beta strand

61 – 64

4

Beta strand

91 – 95

5

Beta strand

99 – 101

3

Beta strand

104 – 107

4

Beta strand

111 – 114

4

Beta strand

117 – 120

4

Beta strand

128 – 132

5

Beta strand

136 – 138

3

Beta strand

141 – 144

4

Beta strand

155 – 157

3

Beta strand

167 – 171

5

Sequences

	Sequence		Length	Mass (Da)
	O00300 [UniParc]. Last modified February 8, 2011. Version 3. Checksum: 2A23AC07BFA1E2DE	FASTA	401	46,026
	10 20 30 40 50 60 MNNLLCCALV 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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT LYS-3. 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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT LYS-3. 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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT LYS-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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT LYS-3. 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]. Tissue: Lung.
[6]	NIEHS SNPs program Submitted (NOV-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS LYS-3 AND MET-104.
[7]	"DNA sequence and analysis of human chromosome 8." Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M., Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S., Asakawa T. , Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A., Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III, Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K., Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P., Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H., Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B., O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K., Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L., Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G., Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W., Platzer M., Shimizu N., Lander E.S. Nature 439:331-335(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[8]	"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]. Tissue: Eye.
[9]	"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] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 22-36 AND 378-401.
[10]	"Signal peptide prediction based on analysis of experimentally verified cleavage sites." Zhang Z., Henzel W.J. Protein Sci. 13:2819-2824(2004) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 22-36.
[11]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 22-393. Tissue: Placenta.
[12]	"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] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 242-255; 354-359 AND 369-378, FUNCTION.
[13]	"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] [Europe PMC] [Abstract] Cited for: INTERACTION WITH TNFSF10.
[14]	"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] [Europe PMC] [Abstract] Cited for: CHARACTERIZATION, MUTAGENESIS OF CYS-400.
[15]	"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] [Europe PMC] [Abstract] Cited for: REVIEW.
[16]	"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 22-186 IN COMPLEX WITH TNFSF11, INTERACTION WITH TNFSF11, SUBUNIT, FUNCTION, MUTAGENESIS OF 78-ASP-GLU-79 AND GLU-116, GLYCOSYLATION AT ASN-178, DISULFIDE BONDS.
[17]	"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] [Europe PMC] [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

EMBL
GenBank
DDBJ

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.
AC107953 Genomic DNA. No translation available.
AP004283 Genomic DNA. No translation available.
BC030155 mRNA. Translation: AAH30155.1.
AF134187 mRNA. Translation: AAF20168.1.

IPI

IPI00298362.

RefSeq

NP_002537.3. NM_002546.3.

UniGene

Hs.81791.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3URF	X-ray	2.70	Z	22-186	[»]

ProteinModelPortal

O00300.

SMR

O00300. Positions 26-186.

ModBase

Search...

Protein-protein interaction databases

STRING

9606.ENSP00000297350.

PTM databases

PhosphoSite

O00300.

Proteomic databases

PaxDb

O00300.

PRIDE

O00300.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000297350; ENSP00000297350; ENSG00000164761.

GeneID

4982.

KEGG

hsa:4982.

UCSC

uc003yon.4. human.

Organism-specific databases

CTD

4982.

GeneCards

GC08M119935.

H-InvDB

HIX0007748.

HGNC

HGNC:11909. TNFRSF11B.

HPA

HPA027013.

MIM

239000. phenotype.
602643. gene.

neXtProt

NX_O00300.

Orphanet

2801. Juvenile Paget's disease.

PharmGKB

PA36602.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG80702.

HOGENOM

HOG000273896.

HOVERGEN

HBG061495.

InParanoid

O00300.

KO

K05148.

OMA

DIDLCEN.

OrthoDB

EOG49W2FD.

Gene expression databases

ArrayExpress

O00300.

Bgee

O00300.

CleanEx

HS_TNFRSF11B.

Genevestigator

O00300.

GermOnline

ENSG00000164761. Homo sapiens.

Family and domain databases

Gene3D

1.10.533.10. 1 hit.

InterPro

IPR011029. DEATH-like_dom.
IPR000488. Death_domain.
IPR001368. TNFR/NGFR_Cys_rich_reg.
IPR022323. TNFR_11.
IPR017371. TNFR_11B.
[Graphical view]

PANTHER

PTHR23097:SF36. PTHR23097:SF36. 1 hit.

Pfam

PF00531. Death. 1 hit.
PF00020. TNFR_c6. 2 hits.
[Graphical view]

PIRSF

PIRSF038065. TNFR_11B. 1 hit.

PRINTS

PR01961. TNFACTORR11.
PR01975. TNFACTORR11B.

SMART

SM00208. TNFR. 4 hits.
[Graphical view]

SUPFAM

SSF47986. DEATH_like. 1 hit.

PROSITE

PS50017. DEATH_DOMAIN. False negative.
PS00652. TNFR_NGFR_1. 1 hit.
PS50050. TNFR_NGFR_2. 2 hits.
[Graphical view]

ProtoNet

Search...

Other

GenomeRNAi

4982.

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:	February 8, 2011
Last modified:	May 1, 2013
This is version 121 of the entry and version 3 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.