O14788 (TNF11_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Tumor necrosis factor ligand superfamily member 11

Alternative name(s):
Osteoclast differentiation factor
Short name=ODF
Osteoprotegerin ligand
Short name=OPGL
Receptor activator of nuclear factor kappa-B ligand
Short name=RANKL
TNF-related activation-induced cytokine
Short name=TRANCE
CD_antigen=CD254

Cleaved into the following 2 chains:

1. Tumor necrosis factor ligand superfamily member 11, membrane form
2. Tumor necrosis factor ligand superfamily member 11, soluble form

Gene names

Name:	TNFSF11
Synonyms:	OPGL, RANKL, TRANCE

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	317 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	Cytokine that binds to TNFRSF11B/OPG and to TNFRSF11A/RANK. Osteoclast differentiation and activation factor. Augments the ability of dendritic cells to stimulate naive T-cell proliferation. May be an important regulator of interactions between T-cells and dendritic cells and may play a role in the regulation of the T-cell-dependent immune response. May also play an important role in enhanced bone-resorption in humoral hypercalcemia of malignancy. Ref.7
Subunit structure	Homotrimer Probable. Interacts with TNFRSF11B. Ref.7
Subcellular location	Isoform 1: Cell membrane; Single-pass type II membrane protein. Isoform 3: Cell membrane; Single-pass type II membrane protein. Isoform 2: Cytoplasm By similarity. Tumor necrosis factor ligand superfamily member 11, soluble form: Secreted By similarity.
Tissue specificity	Highest in the peripheral lymph nodes, weak in spleen, peripheral blood Leukocytes, bone marrow, heart, placenta, skeletal muscle, stomach and thyroid.
Induction	Up-regulated by T-cell receptor stimulation.
Post-translational modification	The soluble form of isoform 1 derives from the membrane form by proteolytic processing By similarity. The cleavage may be catalyzed by ADAM17.
Involvement in disease	Osteopetrosis autosomal recessive 2 (OPTB2) [MIM:259710]: 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. OPTB2 is characterized by paucity of osteoclasts, suggesting a molecular defect in osteoclast development. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.8
Sequence similarities	Belongs to the tumor necrosis factor family.

Ontologies

Keywords
Biological process	Differentiation
Cellular component	Cell membrane Cytoplasm Membrane Secreted
Coding sequence diversity	Alternative splicing
Disease	Disease mutation Osteopetrosis
Domain	Signal-anchor Transmembrane Transmembrane helix
Molecular function	Cytokine Developmental protein Receptor
PTM	Glycoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	ERK1 and ERK2 cascade Inferred from electronic annotation. Source: Compara activation of JUN kinase activity Inferred from electronic annotation. Source: Compara bone resorption Inferred from electronic annotation. Source: Compara immune response Non-traceable author statement Ref.6. Source: UniProtKB mammary gland alveolus development Inferred from electronic annotation. Source: Compara mammary gland epithelial cell proliferation Inferred from electronic annotation. Source: Compara monocyte chemotaxis Inferred from direct assay PubMed 15248232. Source: BHF-UCL organ morphogenesis Inferred from electronic annotation. Source: Compara ossification Inferred from electronic annotation. Source: Compara osteoclast differentiation Non-traceable author statement Ref.2. Source: UniProtKB positive regulation of ERK1 and ERK2 cascade via TNFSF11-mediated signaling Inferred from direct assay PubMed 18606301. Source: BHF-UCL positive regulation of I-kappaB kinase/NF-kappaB cascade Inferred from electronic annotation. Source: Compara positive regulation of JNK cascade Inferred from electronic annotation. Source: Compara positive regulation of MAP kinase activity Inferred from direct assay PubMed 15304486. Source: BHF-UCL positive regulation of NF-kappaB transcription factor activity Inferred from direct assay Ref.1. Source: BHF-UCL positive regulation of T cell activation Inferred from direct assay Ref.1. Source: BHF-UCL positive regulation of bone resorption Inferred from direct assay PubMed 17241109. Source: UniProtKB positive regulation of corticotropin-releasing hormone secretion Inferred from sequence or structural similarity PubMed 19940926. Source: BHF-UCL 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 homotypic cell-cell adhesion Inferred from direct assay Ref.1. Source: BHF-UCL positive regulation of osteoclast differentiation Inferred from direct assay PubMed 17241109. Source: UniProtKB positive regulation of protein kinase B signaling cascade Inferred from electronic annotation. Source: Compara positive regulation of transcription from RNA polymerase II promoter Inferred from direct assay PubMed 15304486. Source: BHF-UCL protein homooligomerization Inferred from electronic annotation. Source: Compara
Cellular_component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell extracellular region Non-traceable author statement Ref.4Ref.2. Source: UniProtKB extracellular space Inferred from electronic annotation. Source: UniProtKB-KW integral to plasma membrane Non-traceable author statement Ref.6. Source: UniProtKB
Molecular_function	cytokine activity Non-traceable author statement Ref.2. Source: UniProtKB tumor necrosis factor receptor binding Non-traceable author statement Ref.6Ref.1. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: O14788-1)

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: O14788-2)

Also known as: SODF;

The sequence of this isoform differs from the canonical sequence as follows:
     1-73: Missing.

Isoform 3 (identifier: O14788-3)

The sequence of this isoform differs from the canonical sequence as follows:
     1-47: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 317

317

Tumor necrosis factor ligand superfamily member 11, membrane form

PRO_0000034514

Chain

140 – 317

178

Tumor necrosis factor ligand superfamily member 11, soluble form By similarity

PRO_0000034515

Regions

Topological domain

1 – 47

47

Cytoplasmic Potential

Transmembrane

48 – 68

21

Helical; Signal-anchor for type II membrane protein; Potential

Topological domain

69 – 317

249

Extracellular Potential

Sites

Site

139 – 140

2

Cleavage By similarity

Amino acid modifications

Glycosylation

171

1

N-linked (GlcNAc...) Potential

Glycosylation

198

1

N-linked (GlcNAc...) Potential

Natural variations

Alternative sequence

1 – 73

73

Missing in isoform 2.

VSP_006447

Alternative sequence

1 – 47

47

Missing in isoform 3.

VSP_006446

Natural variant

199

1

M → K in OPTB2. Ref.8

VAR_037424

Experimental info

Mutagenesis

223

1

R → A: Reduces affinity for TNFRSF11B. Ref.7

Mutagenesis

257

1

K → A: Reduces affinity for TNFRSF11B. Ref.7

Sequence conflict

194

1

A → G in AAC51762. Ref.6

Secondary structure

1

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317

Helix Strand Turn

Details...

Beta strand

165 – 170

6

Beta strand

182 – 184

3

Beta strand

187 – 191

5

Beta strand

194 – 202

9

Beta strand

205 – 208

4

Beta strand

212 – 225

14

Beta strand

227 – 229

3

Beta strand

235 – 248

14

Beta strand

253 – 263

11

Beta strand

269 – 283

15

Beta strand

287 – 294

8

Helix

296 – 298

3

Turn

303 – 305

3

Beta strand

306 – 314

9

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified January 1, 1998. Version 1. Checksum: 766176446348097F	FASTA	317	35,478
	10 20 30 40 50 60 MRRASRDYTK YLRGSEEMGG GPGAPHEGPL HAPPPPAPHQ PPAASRSMFV ALLGLGLGQV 70 80 90 100 110 120 VCSVALFFYF RAQMDPNRIS EDGTHCIYRI LRLHENADFQ DTTLESQDTK LIPDSCRRIK 130 140 150 160 170 180 QAFQGAVQKE LQHIVGSQHI RAEKAMVDGS WLDLAKRSKL EAQPFAHLTI NATDIPSGSH 190 200 210 220 230 240 KVSLSSWYHD RGWAKISNMT FSNGKLIVNQ DGFYYLYANI CFRHHETSGD LATEYLQLMV 250 260 270 280 290 300 YVTKTSIKIP SSHTLMKGGS TKYWSGNSEF HFYSINVGGF FKLRSGEEIS IEVSNPSLLD 310 PDQDATYFGA FKVRDID
	Isoform 2 (SODF) [UniParc]. Checksum: C827590684B6B83C	FASTA	244	27,690
	10 20 30 40 50 60 MDPNRISEDG THCIYRILRL HENADFQDTT LESQDTKLIP DSCRRIKQAF QGAVQKELQH 70 80 90 100 110 120 IVGSQHIRAE KAMVDGSWLD LAKRSKLEAQ PFAHLTINAT DIPSGSHKVS LSSWYHDRGW 130 140 150 160 170 180 AKISNMTFSN GKLIVNQDGF YYLYANICFR HHETSGDLAT EYLQLMVYVT KTSIKIPSSH 190 200 210 220 230 240 TLMKGGSTKY WSGNSEFHFY SINVGGFFKL RSGEEISIEV SNPSLLDPDQ DATYFGAFKV RDID
	Isoform 3 [UniParc]. Checksum: 5C7754CE32E6F368	FASTA	270	30,523
	10 20 30 40 50 60 MFVALLGLGL GQVVCSVALF FYFRAQMDPN RISEDGTHCI YRILRLHENA DFQDTTLESQ 70 80 90 100 110 120 DTKLIPDSCR RIKQAFQGAV QKELQHIVGS QHIRAEKAMV DGSWLDLAKR SKLEAQPFAH 130 140 150 160 170 180 LTINATDIPS GSHKVSLSSW YHDRGWAKIS NMTFSNGKLI VNQDGFYYLY ANICFRHHET 190 200 210 220 230 240 SGDLATEYLQ LMVYVTKTSI KIPSSHTLMK GGSTKYWSGN SEFHFYSINV GGFFKLRSGE 250 260 270 EISIEVSNPS LLDPDQDATY FGAFKVRDID

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] (ISOFORM 1). Tissue: Bone marrow and Peripheral blood.
[2]	"Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation." Lacey D.L., Timms E., Tan H.-L., Kelley M.J., Dunstan C.R., Burgess T., Elliott R., Colombero A., Elliott G., Scully S., Hsu H., Sullivan J., Hawkins N., Davy E., Capparelli C., Eli A., Qian Y.-X., Kaufman S. , Sarosi I., Shalhoub V., Senaldi G., Guo J., Delaney J., Boyle W.J. Cell 93:165-176(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Lymph node.
[3]	"Determination of human RANKL isoforms." Ikeda T., Kuroyama H., Hirokawa K. Submitted (JUN-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 3).
[4]	"Cancer cells responsible for humoral hypercalcemia express mRNA encoding a secreted form of ODF/TRANCE that induces osteoclast formation." Nagai M., Kyakumoto S., Sato N. Biochem. Biophys. Res. Commun. 269:532-536(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). Tissue: Tongue.
[5]	"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] (ISOFORM 1). Tissue: Lung.
[6]	"TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells." Wong B.R., Rho J., Arron J., Robinson E., Orlinick J., Chao M., Kalachikov S., Cayani E., Bartlett F.S. III, Frankel W.N., Lee S.Y., Choi Y. J. Biol. Chem. 272:25190-25194(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 73-317. Tissue: Thymocyte.
[7]	"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 162-317 IN COMPLEX WITH TNFRSF11B, FUNCTION, MUTAGENESIS OF ARG-223 AND LYS-257, INTERACTION WITH TNFRSF11B.
[8]	"Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL." Sobacchi C., Frattini A., Guerrini M.M., Abinun M., Pangrazio A., Susani L., Bredius R., Mancini G., Cant A., Bishop N., Grabowski P., Del Fattore A., Messina C., Errigo G., Coxon F.P., Scott D.I., Teti A., Rogers M.J. , Vezzoni P., Villa A., Helfrich M.H. Nat. Genet. 39:960-962(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT OPTB2 LYS-199.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF019047 mRNA. Translation: AAB86811.1.
AF053712 mRNA. Translation: AAC39731.1.
AB064269 mRNA. Translation: BAB79694.1.
AB061227 mRNA. Translation: BAB71768.1.
AB064270 mRNA. Translation: BAB79695.1.
AB037599 mRNA. Translation: BAA90488.1.
BC074823 mRNA. Translation: AAH74823.1.
BC074890 mRNA. Translation: AAH74890.1.
AF013171 mRNA. Translation: AAC51762.1.

IPI

IPI00023732.
IPI00219810.
IPI00219811.

RefSeq

NP_003692.1. NM_003701.3.
NP_143026.1. NM_033012.3.

UniGene

Hs.333791.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3URF	X-ray	2.70	A	162-317	[»]

ProteinModelPortal

O14788.

ModBase

Search...

Protein-protein interaction databases

MINT

MINT-8247611.

STRING

9606.ENSP00000239849.

PTM databases

PhosphoSite

O14788.

Proteomic databases

PaxDb

O14788.

PRIDE

O14788.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000239849; ENSP00000239849; ENSG00000120659.
ENST00000358545; ENSP00000351347; ENSG00000120659.
ENST00000398795; ENSP00000381775; ENSG00000120659.
ENST00000405262; ENSP00000384042; ENSG00000120659.
ENST00000544862; ENSP00000444913; ENSG00000120659.

GeneID

8600.

KEGG

hsa:8600.

UCSC

uc001uyt.2. human.

Organism-specific databases

CTD

8600.

GeneCards

GC13P043136.

HGNC

HGNC:11926. TNFSF11.

HPA

CAB009193.

MIM

259710. phenotype.
602642. gene.

neXtProt

NX_O14788.

Orphanet

667. Autosomal recessive malignant osteopetrosis.

PharmGKB

PA36619.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG40842.

HOGENOM

HOG000132981.

HOVERGEN

HBG054257.

InParanoid

O14788.

KO

K05473.

OMA

GKLIVNQ.

PhylomeDB

O14788.

Enzyme and pathway databases

Pathway_Interaction_DB

il6_7pathway. IL6-mediated signaling events.

Gene expression databases

ArrayExpress

O14788.

Bgee

O14788.

CleanEx

HS_TNFSF11.

Genevestigator

O14788.

GermOnline

ENSG00000120659. Homo sapiens.

Family and domain databases

Gene3D

2.60.120.40. 1 hit.

InterPro

IPR006052. TNF.
IPR017355. TNF_ligand_10/11.
IPR008983. Tumour_necrosis_fac-like_dom.
[Graphical view]

Pfam

PF00229. TNF. 1 hit.
[Graphical view]

PIRSF

PIRSF038013. TNF10_TNF11. 1 hit.

SMART

SM00207. TNF. 1 hit.
[Graphical view]

SUPFAM

SSF49842. TNF_like. 1 hit.

PROSITE

PS00251. TNF_1. False negative.
PS50049. TNF_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

GenomeRNAi

8600.

NextBio

32221.

PMAP-CutDB

O14788.

SOURCE

Search...

Entry information

Entry name

TNF11_HUMAN

Accession

Primary (citable) accession number: O14788
Secondary accession number(s): O14723, Q96Q17, Q9P2Q3

Entry history

Integrated into UniProtKB/Swiss-Prot:	January 24, 2001
Last sequence update:	January 1, 1998
Last modified:	May 29, 2013
This is version 125 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.