Reviewed, UniProtKB/Swiss-Prot O35235 (TNF11_MOUSE)

Names and origin

Protein names

Recommended name:
    Tumor necrosis factor ligand superfamily member 11
Alternative name(s):
    Receptor activator of nuclear factor kappa B ligand
      Short name=RANKL
    TNF-related activation-induced cytokine
      Short name=TRANCE
    Osteoprotegerin ligand
      Short name=OPGL
    Osteoclast differentiation factor
      Short name=ODF
    CD_antigen=CD254
Cleaved into the following 2 chains:
    1- Recommended name:
            Tumor necrosis factor ligand superfamily member 11, membrane form
    2- Recommended name:
            Tumor necrosis factor ligand superfamily member 11, soluble form

Gene names

Name:	Tnfsf11
Synonyms:	Opgl, Rankl, Trance

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus

Protein attributes

Sequence length	316 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.
Subunit structure	Homotrimer.
Subcellular location	Isoform 1: Cell membrane; Single-pass type II membrane protein. Isoform 2: Cell membrane; Single-pass type II membrane protein. Isoform 3: Cytoplasm. Tumor necrosis factor ligand superfamily member 11, soluble form: Secreted.
Tissue specificity	Highly expressed in thymus and lymph nodes, but not in non-lymphoid tissues and is abundantly expressed in T-cells but not in B-cells. A high level expression is also seen in the trabecular bone and lung.
Post-translational modification	N-glycosylated. Ref.7 The soluble form of isoform 1 derives from the membrane form by proteolytic processing. The cleavage may be catalyzed by ADAM17. A further shorter soluble form was observed.
Involvement in disease	Deficiency in Tnfsf11 results in failure to form lobulo-alveolar mammary structures during pregnancy, resulting in death of newborns. Trance-deficient mice show severe osteopetrosis, with no osteoclasts, marrow spaces, or tooth eruption, and exhibit profound growth retardation at several skeletal sites, including the limbs, skull, and vertebrae and have marked chondrodysplasia, with thick, irregular growth plates and a relative increase in hypertrophic chondrocytes.
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
Domain	Signal-anchor Transmembrane
Molecular function	Cytokine Developmental protein Receptor
PTM	Glycoprotein
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	bone resorption Inferred from direct assay. Source: MGI immune response Inferred from electronic annotation. Source: InterPro lymph node development Traceable author statement. Source: MGI organ morphogenesis Inferred from mutant phenotype. Source: MGI ossification Inferred from mutant phenotype. Source: MGI osteoclast differentiation Inferred from direct assay. Source: MGI positive regulation of osteoclast differentiation Inferred from direct assay. Source: MGI protein homooligomerization Inferred from direct assay. Source: MGI
Cellular component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell extracellular space Inferred from electronic annotation. Source: UniProtKB-KW integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	cytokine activity Inferred from electronic annotation. Source: UniProtKB-KW receptor activity Inferred from electronic annotation. Source: UniProtKB-KW tumor necrosis factor receptor binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Alternative products

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

Isoform 1 (identifier: O35235-1)

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: O35235-2)

The sequence of this isoform differs from the canonical sequence as follows:
     14-44: SSEEMGSGPGVPHEGPLHPAPSAPAPAPPPA → TP

Isoform 3 (identifier: O35235-3)

The sequence of this isoform differs from the canonical sequence as follows:
     1-117: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 316

316

Tumor necrosis factor ligand superfamily member 11, membrane form

PRO_0000034516

Chain

139 – 316

178

Tumor necrosis factor ligand superfamily member 11, soluble form

PRO_0000034517

Regions

Topological domain

1 – 48

48

Cytoplasmic Potential

Transmembrane

49 – 69

21

Signal-anchor for type II membrane protein Potential

Topological domain

70 – 316

247

Extracellular Potential

Sites

Site

138 – 139

2

Cleavage

Amino acid modifications

Glycosylation

197

1

N-linked (GlcNAc...) Potential

Glycosylation

262

1

N-linked (GlcNAc...) Potential

Natural variations

Alternative sequence

1 – 117

117

Missing in isoform 3.

VSP_006448

Alternative sequence

14 – 44

31

SSEEM…APPPA → TP in isoform 2.

VSP_006449

Experimental info

Sequence conflict

99

1

G → D in AAB86812. Ref.2

Sequence conflict

141 – 143

3

Missing in BAA36970. Ref.5

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

316

Helix Strand Turn

Details...

Beta strand

164 – 169

6

Beta strand

186 – 190

5

Beta strand

194 – 201

8

Beta strand

204 – 207

4

Beta strand

211 – 224

14

Helix

225 – 227

3

Beta strand

233 – 248

16

Beta strand

252 – 262

11

Beta strand

267 – 282

16

Beta strand

286 – 293

8

Helix

295 – 297

3

Turn

302 – 304

3

Beta strand

305 – 313

9

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified January 1, 1998. Version 1. Checksum: 08DF63A2BE00967A	FASTA	316	34,945
	10 20 30 40 50 60 MRRASRDYGK YLRSSEEMGS GPGVPHEGPL HPAPSAPAPA PPPAASRSMF LALLGLGLGQ 70 80 90 100 110 120 VVCSIALFLY FRAQMDPNRI SEDSTHCFYR ILRLHENAGL QDSTLESEDT LPDSCRRMKQ 130 140 150 160 170 180 AFQGAVQKEL QHIVGPQRFS GAPAMMEGSW LDVAQRGKPE AQPFAHLTIN AASIPSGSHK 190 200 210 220 230 240 VTLSSWYHDR GWAKISNMTL SNGKLRVNQD GFYYLYANIC FRHHETSGSV PTDYLQLMVY 250 260 270 280 290 300 VVKTSIKIPS SHNLMKGGST KNWSGNSEFH FYSINVGGFF KLRAGEEISI QVSNPSLLDP 310 DQDATYFGAF KVQDID
	Isoform 2. Checksum: 8B2CE8E4C7B534CC	FASTA	287	32,235
	10 20 30 40 50 60 MRRASRDYGK YLRTPASRSM FLALLGLGLG QVVCSIALFL YFRAQMDPNR ISEDSTHCFY 70 80 90 100 110 120 RILRLHENAG LQDSTLESED TLPDSCRRMK QAFQGAVQKE LQHIVGPQRF SGAPAMMEGS 130 140 150 160 170 180 WLDVAQRGKP EAQPFAHLTI NAASIPSGSH KVTLSSWYHD RGWAKISNMT LSNGKLRVNQ 190 200 210 220 230 240 DGFYYLYANI CFRHHETSGS VPTDYLQLMV YVVKTSIKIP SSHNLMKGGS TKNWSGNSEF 250 260 270 280 HFYSINVGGF FKLRAGEEIS IQVSNPSLLD PDQDATYFGA FKVQDID
	Isoform 3. Checksum: 401C13EB5E8CE166	FASTA	199	22,150
	10 20 30 40 50 60 MKQAFQGAVQ KELQHIVGPQ RFSGAPAMME GSWLDVAQRG KPEAQPFAHL TINAASIPSG 70 80 90 100 110 120 SHKVTLSSWY HDRGWAKISN MTLSNGKLRV NQDGFYYLYA NICFRHHETS GSVPTDYLQL 130 140 150 160 170 180 MVYVVKTSIK IPSSHNLMKG GSTKNWSGNS EFHFYSINVG GFFKLRAGEE ISIQVSNPSL 190 LDPDQDATYF GAFKVQDID

References

[1]	"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: 9312132] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Hybridoma.
[2]	"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: 9367155] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Thymic lymphoma.
[3]	"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: 9568710] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Bone marrow.
[4]	"Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL." Yasuda H., Shima N., Nakagawa N., Yamaguchi K., Kinosaki M., Mochizuki S., Tomoyasu A., Yano K., Goto M., Murakami A., Tsuda E., Morinaga T., Higashio K., Udagawa N., Takahashi N., Suda T. Proc. Natl. Acad. Sci. U.S.A. 95:3597-3602(1998) [PubMed: 9520411] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Bone marrow stroma.
[5]	"Cloning and characterization of the gene encoding mouse osteoclast differentiation factor." Kodaira K., Kodaira K., Mizuno A., Yasuda H., Shima N., Murakami A., Ueda M., Higashio K. Gene 230:121-127(1999) [PubMed: 10196481] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1). Strain: 129.
[6]	"Determination of three isoforms of the receptor activator of nuclear factor-kappaB ligand and their differential expression in bone and thymus." Ikeda T., Kasai M., Utsuyama M., Hirokawa K. Endocrinology 142:1419-1426(2001) [PubMed: 11250921] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 3).
[7]	"Evidence for a role of a tumor necrosis factor-alpha (TNF-alpha)-converting enzyme-like protease in shedding of TRANCE, a TNF family member involved in osteoclastogenesis and dendritic cell survival." Lum L., Wong B.R., Josien R., Becherer J.D., Erdjument-Bromage H., Schloendorff J., Tempst P., Choi Y., Blobel C.P. J. Biol. Chem. 274:13613-13618(1999) [PubMed: 10224132] [Abstract] Cited for: PROTEIN SEQUENCE OF 139-147, PROTEOLYTIC PROCESSING, GLYCOSYLATION.
[8]	"Crystal structure of the TRANCE/RANKL cytokine reveals determinants of receptor-ligand specificity." Lam J., Nelson C.A., Ross F.P., Teitelbaum S.L., Fremont D.H. J. Clin. Invest. 108:971-979(2001) [PubMed: 11581298] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 158-316.
[9]	"Crystal structure of the extracellular domain of mouse RANK ligand at 2.2-A resolution." Ito S., Wakabayashi K., Ubukata O., Hayashi S., Okada F., Hata T. J. Biol. Chem. 277:6631-6636(2002) [PubMed: 11733492] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 137-316.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBLGenBankDDBJ

AF013170 mRNA. Translation: AAC71061.1.
AF019048 mRNA. Translation: AAB86812.1.
AF053713 mRNA. Translation: AAC40113.1.
AB008426 mRNA. Translation: BAA25425.1.
AB022039 Genomic DNA. Translation: BAA36970.1.
AB032771 mRNA. Translation: BAA97257.1.
AB032772 mRNA. Translation: BAA97258.1.
AB036798 mRNA. Translation: BAA97259.1.

IPI

IPI00128604.
IPI00227894.
IPI00875021.

UniGene

Mm.249221

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1IQA	X-ray	2.20	A/B/C	157-316	[»]
1JTZ	X-ray	2.60	X/Y/Z	156-316	[»]
1S55	X-ray	1.90	A/B/C	161-316	[»]

ModBase

Search...

Genome annotation databases

Ensembl

ENSMUSG00000022015. Mus musculus. [Contig view]

Organism-specific databases

MGI

MGI:1100089. Tnfsf11.

Phylogenomic databases

HOGENOM

O35235.

HOVERGEN

O35235.

Gene expression databases

ArrayExpress

O35235.

Bgee

O35235.

GermOnline

ENSMUSG00000022015. Mus musculus.

Family and domain databases

InterPro

IPR017355. TNF10_TNF11.
IPR006052. TNF_family.
IPR008983. Tumour_necrosis_fac-like.
[Graphical view]

Gene3D

G3DSA:2.60.120.40. Tumour_necrosis_fac-like. 1 hit.

Pfam

PF00229. TNF. 1 hit.
[Graphical view]

PIRSF

PIRSF038013. TNF10_TNF11. 1 hit.

ProDom

PD002012. TNF_subf. 1 hit.
[Graphical view] [Entries sharing at least one domain]

SMART

SM00207. TNF. 1 hit.
[Graphical view]

PROSITE

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

ProtoNet

Search...

Other Resources

SOURCE

Search...

Entry information

Entry name

TNF11_MOUSE

Accession

Primary (citable) accession number: O35235
Secondary accession number(s): O35306 , Q9JJK8, Q9JJK9, Q9R1Y0

Entry history

Integrated into UniProtKB/Swiss-Prot:	January 24, 2001
Last sequence update:	January 1, 1998
Last modified:	June 16, 2009
This is version 95 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)