P50591 (TNF10_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Tumor necrosis factor ligand superfamily member 10

Alternative name(s):
Apo-2 ligand
Short name=Apo-2L
TNF-related apoptosis-inducing ligand
Short name=Protein TRAIL
CD_antigen=CD253

Gene names

Name:	TNFSF10
Synonyms:	APO2L, TRAIL

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	281 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Cytokine that binds to TNFRSF10A/TRAILR1, TNFRSF10B/TRAILR2, TNFRSF10C/TRAILR3, TNFRSF10D/TRAILR4 and possibly also to TNFRSF11B/OPG. Induces apoptosis. Its activity may be modulated by binding to the decoy receptors TNFRSF10C/TRAILR3, TNFRSF10D/TRAILR4 and TNFRSF11B/OPG that cannot induce apoptosis.
Cofactor	Binds 1 zinc ion per trimer.
Subunit structure	Homotrimer.
Subcellular location	Membrane; Single-pass type II membrane protein Potential.
Tissue specificity	Widespread; most predominant in spleen, lung and prostate.
Sequence similarities	Belongs to the tumor necrosis factor family.

Ontologies

Keywords
Biological process	Apoptosis
Cellular component	Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Signal-anchor Transmembrane Transmembrane helix
Ligand	Metal-binding Zinc
Molecular function	Cytokine
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	activation of cysteine-type endopeptidase activity involved in apoptotic process Traceable author statement. Source: Reactome apoptotic signaling pathway Traceable author statement. Source: Reactome cell-cell signaling Traceable author statement Ref.1. Source: ProtInc immune response Inferred from electronic annotation. Source: InterPro induction of apoptosis Traceable author statement Ref.2. Source: ProtInc positive regulation of I-kappaB kinase/NF-kappaB cascade Inferred from expression pattern PubMed 12761501. Source: UniProtKB positive regulation of extrinsic apoptotic signaling pathway Inferred from direct assay PubMed 20097879PubMed 21525171PubMed 22266862. Source: UniProtKB positive regulation of release of cytochrome c from mitochondria Inferred from direct assay PubMed 22266862. Source: UniProtKB
Cellular_component	extracellular region Traceable author statement. Source: Reactome extracellular space Inferred from electronic annotation. Source: UniProtKB-KW integral to plasma membrane Traceable author statement Ref.2. Source: ProtInc
Molecular_function	metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW receptor binding Traceable author statement Ref.2Ref.1. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CUL3	Q13618	2	EBI-495373,EBI-456129
TNFRSF10A	O00220	8	EBI-495373,EBI-518861
TNFRSF10B	O14763	23	EBI-495373,EBI-518882

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P50591-1)

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: P50591-2)

Also known as: TRAIL-short; TRAIL-s;

The sequence of this isoform differs from the canonical sequence as follows:
     91-101: MILRTSEETIS → TPRMKRLWAAK
     102-281: Missing.

Note: Induced upon HIV infection, antagonizes signaling via TRAIL receptor R2 (TNFRSF10B).

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 281

281

Tumor necrosis factor ligand superfamily member 10

PRO_0000185503

Regions

Topological domain

1 – 17

17

Cytoplasmic Potential

Transmembrane

18 – 38

21

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

Topological domain

39 – 281

243

Extracellular Potential

Sites

Metal binding

230

1

Zinc

Natural variations

Alternative sequence

91 – 101

11

MILRTSEETIS → TPRMKRLWAAK in isoform 2.

VSP_043507

Alternative sequence

102 – 281

180

Missing in isoform 2.

VSP_043508

Natural variant

33

1

V → I.
Corresponds to variant rs6763816 [ dbSNP | Ensembl ].

VAR_052584

Natural variant

47

1

D → E.
Corresponds to variant rs16845759 [ dbSNP | Ensembl ].

VAR_052585

Secondary structure

1

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281

Helix Strand Turn

Details...

Beta strand

123 – 127

5

Turn

137 – 139

3

Beta strand

144 – 146

3

Beta strand

148 – 150

3

Turn

158 – 161

4

Beta strand

163 – 170

8

Beta strand

173 – 178

6

Beta strand

180 – 193

14

Beta strand

205 – 213

9

Beta strand

215 – 218

4

Beta strand

220 – 228

9

Beta strand

237 – 250

14

Beta strand

255 – 262

8

Helix

263 – 265

3

Turn

270 – 272

3

Beta strand

273 – 279

7

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified October 1, 1996. Version 1. Checksum: DDAAAF78DAAB2F6D	FASTA	281	32,509
	10 20 30 40 50 60 MAMMEVQGGP SLGQTCVLIV IFTVLLQSLC VAVTYVYFTN ELKQMQDKYS KSGIACFLKE 70 80 90 100 110 120 DDSYWDPNDE ESMNSPCWQV KWQLRQLVRK MILRTSEETI STVQEKQQNI SPLVRERGPQ 130 140 150 160 170 180 RVAAHITGTR GRSNTLSSPN SKNEKALGRK INSWESSRSG HSFLSNLHLR NGELVIHEKG 190 200 210 220 230 240 FYYIYSQTYF RFQEEIKENT KNDKQMVQYI YKYTSYPDPI LLMKSARNSC WSKDAEYGLY 250 260 270 280 SIYQGGIFEL KENDRIFVSV TNEHLIDMDH EASFFGAFLV G
	Isoform 2 (TRAIL-short) (TRAIL-s) [UniParc]. Checksum: 205B6BA004A7C104	FASTA	101	11,746
	10 20 30 40 50 60 MAMMEVQGGP SLGQTCVLIV IFTVLLQSLC VAVTYVYFTN ELKQMQDKYS KSGIACFLKE 70 80 90 100 DDSYWDPNDE ESMNSPCWQV KWQLRQLVRK TPRMKRLWAA K

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Identification and characterization of a new member of the TNF family that induces apoptosis." Wiley S.R., Schooley K., Smolak P.J., Din W.S., Huang C.-P., Nicholl J.K., Sutherland G.R., Davis-Smith T., Rauch C., Smith C.A., Goodwin R.G. Immunity 3:673-682(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]	"Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family." Pitti R.M., Marsters S.A., Ruppert S., Donahue C.J., Moore A., Ashkenazi A. J. Biol. Chem. 271:12687-12690(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Placenta.
[3]	"Isolation of a TRAIL antagonist from the serum of HIV-infected patients." Schnepple D.J., Shepard B., Bren G.D., Cummins N.W., Natesampillai S., Trushin S., Algeciras-Schimnich A., Meng X.W., Sainski A.M., Rizza S.A., Kaufmann S.H., Badley A.D. J. Biol. Chem. 286:35742-35754(2011) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), ALTERNATIVE SPLICING.
[4]	"Novel TRAIL splice variant TRAIL-delta." Woods D.C., Haugen M.J., Johnson A.L. Submitted (SEP-2007) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
[5]	"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] (ISOFORM 2). Tissue: Thalamus.
[6]	"The DNA sequence, annotation and analysis of human chromosome 3." Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J. , Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B., Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H., Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J., Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A. Nature 440:1194-1198(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Lymph.
[8]	"Triggering cell death: the crystal structure of Apo2L/TRAIL in a complex with death receptor 5." Hymowitz S.G., Christinger H.W., Fuh G., Ultsch M., O'Connell M., Kelley R.F., Ashkenazi A., de Vos A.M. Mol. Cell 4:563-571(1999) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 114-281.
[9]	"Structure of the TRAIL-DR5 complex reveals mechanisms conferring specificity in apoptotic initiation." Mongkolsapaya J., Grimes J.M., Chen N., Xu X.-N., Stuart D.I., Jones E.Y., Screaton G.R. Nat. Struct. Biol. 6:1048-1053(1999) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 119-281.
[10]	"2.8 A resolution crystal structure of human TRAIL, a cytokine with selective antitumor activity." Cha S.-S., Kim M.S., Choi Y.H., Sung B.J., Shin N.K., Shin H.C., Sung Y.C., Oh B.-H. Immunity 11:253-261(1999) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 114-281.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U37518 mRNA. Translation: AAC50332.1.
U57059 mRNA. Translation: AAB01233.1.
DQ848564 mRNA. Translation: ABI24016.1.
EU183231 mRNA. Translation: ABW24658.1.
AK296085 mRNA. Translation: BAG58840.1.
AC007919 Genomic DNA. No translation available.
AC016938 Genomic DNA. No translation available.
BC032722 mRNA. Translation: AAH32722.1.

IPI

IPI00000049.
IPI00790933.

RefSeq

NP_001177871.1. NM_001190942.1.
NP_003801.1. NM_003810.3.

UniGene

Hs.478275.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1D0G	X-ray	2.40	A/B/D	114-281	[»]
1D2Q	X-ray	2.80	A/B	114-281	[»]
1D4V	X-ray	2.20	B	119-281	[»]
1DG6	X-ray	1.30	A	91-281	[»]
1DU3	X-ray	2.20	D/E/F/J/K/L	114-281	[»]

ProteinModelPortal

P50591.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-6230N.

IntAct

P50591. 14 interactions.

MINT

MINT-109168.

STRING

9606.ENSP00000241261.

PTM databases

PhosphoSite

P50591.

Polymorphism databases

DMDM

1730015.

Proteomic databases

PaxDb

P50591.

PRIDE

P50591.

Protocols and materials databases

DNASU

8743.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000241261; ENSP00000241261; ENSG00000121858.
ENST00000420541; ENSP00000389931; ENSG00000121858.

GeneID

8743.

KEGG

hsa:8743.

UCSC

uc003fid.3. human.
uc003fie.3. human.

Organism-specific databases

CTD

8743.

GeneCards

GC03M172223.

HGNC

HGNC:11925. TNFSF10.

HPA

CAB002446.

MIM

603598. gene.

neXtProt

NX_P50591.

PharmGKB

PA36618.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG46547.

HOGENOM

HOG000230484.

HOVERGEN

HBG059007.

KO

K04721.

OMA

KWQLRQF.

OrthoDB

EOG4PVP0J.

PhylomeDB

P50591.

Enzyme and pathway databases

Pathway_Interaction_DB

trail_pathway. TRAIL signaling pathway.

Reactome

REACT_578. Apoptosis.

Gene expression databases

ArrayExpress

P50591.

Bgee

P50591.

CleanEx

HS_TNFSF10.

Genevestigator

P50591.

GermOnline

ENSG00000121858. Homo sapiens.

Family and domain databases

Gene3D

2.60.120.40. 1 hit.

InterPro

IPR006052. TNF.
IPR021184. TNF_CS.
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. 1 hit.
PS50049. TNF_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P50591.

ChEMBL

CHEMBL5813.

ChiTaRS

TNFSF10. human.

EvolutionaryTrace

P50591.

GenomeRNAi

8743.

NextBio

32805.

SOURCE

Search...

Entry information

Entry name

TNF10_HUMAN

Accession

Primary (citable) accession number: P50591
Secondary accession number(s): A1Y9B3

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	October 1, 1996
Last modified:	May 29, 2013
This is version 134 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.