P48023 (TNFL6_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Tumor necrosis factor ligand superfamily member 6

Alternative name(s):
Apoptosis antigen ligand
Short name=APTL
CD95 ligand
Short name=CD95-L
Fas antigen ligand
Short name=Fas ligand
CD_antigen=CD178

Cleaved into the following 2 chains:

1. Tumor necrosis factor ligand superfamily member 6, membrane form
2. Tumor necrosis factor ligand superfamily member 6, soluble form

Gene names

Name:	FASLG
Synonyms:	APT1LG1, CD95L, FASL, TNFSF6

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	281 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 TNFRSF6/FAS, a receptor that transduces the apoptotic signal into cells. May be involved in cytotoxic T-cell mediated apoptosis and in T-cell development. TNFRSF6/FAS-mediated apoptosis may have a role in the induction of peripheral tolerance, in the antigen-stimulated suicide of mature T-cells, or both. Binding to the decoy receptor TNFRSF6B/DcR3 modulates its effects.
Subunit structure	Homotrimer Probable. Interacts with ARHGAP9, BAIAP2L1, BTK, CACNB3, CACNB4, CRK, DLG2, DNMBP, DOCK4, EPS8L3, FGR, FYB, FYN, HCK, ITK, ITSN2, KALRN, LYN, MACC1, MIA, MPP4, MYO15A, NCF1, NCK1, NCK2, NCKIPSD, OSTF1, PIK3R1, PSTPIP1, RIMBP3C, SAMSN1, SH3GL3, SH3PXD2B, SH3PXD2A, SH3RF2, SKAP2, SNX33, SNX9, SORBS3, SPTA1, SRC, SRGAP1, SRGAP2, SRGAP3, TEC, TJP3 and YES1. Ref.12 Ref.13
Subcellular location	Cell membrane; Single-pass type II membrane protein. Secreted. Cytoplasmic vesicle lumen. Lysosome lumen. Note: May be released into the extracellular fluid, probably by cleavage form the cell surface. Is internalized into multivesicular bodies of secretory lysosomes after phosphorylation by FGR and monoubiquitination. Ref.12
Post-translational modification	N-glycosylated. The soluble form derives from the membrane form by proteolytic processing. Phosphorylated by FGR on tyrosine residues; this is required for ubiquitination and subsequent internalization. Ref.12 Monoubiquitinated.
Involvement in disease	Defects in FASLG are the cause of autoimmune lymphoproliferative syndrome type 1B (ALPS1B) [MIM:601859]; also known as Canale-Smith syndrome (CSS). ALPS is a childhood syndrome involving hemolytic anemia and thrombocytopenia with massive lymphadenopathy and splenomegaly. Ref.9
Sequence similarities	Belongs to the tumor necrosis factor family.

Ontologies

Keywords
Biological process	Apoptosis
Cellular component	Cell membrane Cytoplasmic vesicle Lysosome Membrane Secreted
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Signal-anchor Transmembrane Transmembrane helix
Molecular function	Cytokine
PTM	Disulfide bond Glycoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	activation of cysteine-type endopeptidase activity involved in apoptotic process Inferred from mutant phenotype. Source: BHF-UCL activation of pro-apoptotic gene products Traceable author statement. Source: Reactome cell-cell signaling Traceable author statement. Source: ProtInc immune response Inferred from electronic annotation. Source: InterPro induction of necroptosis by extracellular signals Inferred from direct assay. Source: BHF-UCL induction of necroptosis of activated-T cells Inferred from direct assay. Source: BHF-UCL necrotic cell death Inferred from direct assay. Source: BHF-UCL negative regulation of angiogenesis Inferred from direct assay. Source: BHF-UCL positive regulation of I-kappaB kinase/NF-kappaB cascade Inferred from expression pattern. Source: UniProtKB signal transduction Traceable author statement. Source: ProtInc
Cellular component	cytoplasmic membrane-bounded vesicle lumen Inferred from electronic annotation. Source: UniProtKB-SubCell extracellular space Inferred from direct assay. Source: BHF-UCL integral to plasma membrane Traceable author statement. Source: ProtInc lysosomal lumen Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	cytokine activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
ITK	Q08881	3	EBI-495538,EBI-968552
SNX33	Q8WV41	2	EBI-495538,EBI-2481535
SNX9	Q9Y5X1	2	EBI-495538,EBI-77848

Alternative products

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

Isoform 1 (identifier: P48023-1)

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: P48023-2)

The sequence of this isoform differs from the canonical sequence as follows:
     117-127: STSQMHTASSL → ATPVHPLKKRS
     128-281: Missing.

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 6, membrane form

PRO_0000034500

Chain

130 – 281

152

Tumor necrosis factor ligand superfamily member 6, soluble form

PRO_0000034501

Regions

Topological domain

1 – 80

80

Cytoplasmic Potential

Transmembrane

81 – 102

22

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

Topological domain

103 – 281

179

Extracellular Potential

Compositional bias

4 – 70

67

Pro-rich

Compositional bias

45 – 65

21

Poly-Pro

Sites

Site

129 – 130

2

Cleavage

Amino acid modifications

Glycosylation

184

1

N-linked (GlcNAc...) Potential

Glycosylation

250

1

N-linked (GlcNAc...) Potential

Glycosylation

260

1

N-linked (GlcNAc...) Potential

Disulfide bond

202 ↔ 233

Potential

Natural variations

Alternative sequence

117 – 127

11

STSQMHTASSL → ATPVHPLKKRS in isoform 2.

VSP_006443

Alternative sequence

128 – 281

154

Missing in isoform 2.

VSP_006444

Natural variant

189

1

Y → S.
Corresponds to variant rs12079514 [ dbSNP | Ensembl ].

VAR_052583

Experimental info

Mutagenesis

206

1

P → D, F or R: Lowers binding to TNFRSF6 and reduces cytotoxicity more than 100-fold. Ref.10

Mutagenesis

218

1

Y → F or R: Lowers binding to TNFRSF6 and abolishes cytotoxicity. Ref.10

Mutagenesis

275

1

F → L: Abolishes binding to TNRFSF6 and cytotoxicity. Ref.10

Secondary structure

1

.

.

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.

.

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.

.

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.

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281

Helix Strand Turn

Details...

Beta strand

146 – 148

3

Beta strand

175 – 177

3

Beta strand

180 – 182

3

Beta strand

187 – 191

5

Beta strand

194 – 198

5

Beta strand

208 – 214

7

Beta strand

216 – 220

5

Beta strand

222 – 228

7

Beta strand

240 – 244

5

Beta strand

247 – 251

5

Beta strand

259 – 263

5

Helix

264 – 266

3

Beta strand

278 – 280

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified February 1, 1996. Version 1. Checksum: A8A6EB358246E9BB	FASTA	281	31,485
	10 20 30 40 50 60 MQQPFNYPYP QIYWVDSSAS SPWAPPGTVL PCPTSVPRRP GQRRPPPPPP PPPLPPPPPP 70 80 90 100 110 120 PPLPPLPLPP LKKRGNHSTG LCLLVMFFMV LVALVGLGLG MFQLFHLQKE LAELRESTSQ 130 140 150 160 170 180 MHTASSLEKQ IGHPSPPPEK KELRKVAHLT GKSNSRSMPL EWEDTYGIVL LSGVKYKKGG 190 200 210 220 230 240 LVINETGLYF VYSKVYFRGQ SCNNLPLSHK VYMRNSKYPQ DLVMMEGKMM SYCTTGQMWA 250 260 270 280 RSSYLGAVFN LTSADHLYVN VSELSLVNFE ESQTFFGLYK L
	Isoform 2 [UniParc]. Checksum: F617D96B26B8E3BA	FASTA	127	14,006
	10 20 30 40 50 60 MQQPFNYPYP QIYWVDSSAS SPWAPPGTVL PCPTSVPRRP GQRRPPPPPP PPPLPPPPPP 70 80 90 100 110 120 PPLPPLPLPP LKKRGNHSTG LCLLVMFFMV LVALVGLGLG MFQLFHLQKE LAELREATPV HPLKKRS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Fas ligand mediates activation-induced cell death in human T lymphocytes." Alderson M. J. Exp. Med. 181:71-77(1995) [PubMed: 7528780] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]	"Human Fas ligand: gene structure, chromosomal location and species specificity." Takahashi T., Tanaka M., Inazawa J., Abe T., Suda T., Nagata S. Int. Immunol. 6:1567-1574(1994) [PubMed: 7826947] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[3]	Schaetzlein C.E., Poehlmann R., Philippsen P., Eibel H. Submitted (JUN-1995) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[4]	"Role of Fas ligand in apoptosis induced by hepatitis C virus infection." Mita E., Hayashi N., Iio S., Takehara T., Hijioka T., Kasahara A., Fusamoto H., Kamada T. Biochem. Biophys. Res. Commun. 204:468-474(1994) [PubMed: 7980502] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[5]	"Isolation and characterization of a new naturally occuring variant of human Fas ligand that is expressed only in membrane bound form." Zeytun A., Nagarkatti M., Nagarkatti P.S. Submitted (JUL-2000) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). Tissue: Leukocyte.
[6]	"The DNA sequence and biological annotation of human chromosome 1." Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R. Nature 441:315-321(2006) [PubMed: 16710414] [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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Blood.
[8]	Matsumura M., Nakanishi Y., Ohba Y. Submitted (APR-1998) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-10. Tissue: Blood.
[9]	"Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease." Wu J., Wilson J., He J., Xiang L., Schur P.H., Mountz J.D. J. Clin. Invest. 98:1107-1113(1996) [PubMed: 8787672] [Abstract] Cited for: INVOLVEMENT IN ALPS1B.
[10]	"Characterization of Fas (Apo-1, CD95)-Fas ligand interaction." Schneider P., Bodmer J.-L., Holler N., Mattmann C., Scuderi P., Terskikh A., Peitsch M.C., Tschopp J. J. Biol. Chem. 272:18827-18833(1997) [PubMed: 9228058] [Abstract] Cited for: CHARACTERIZATION, MUTAGENESIS OF PRO-206; TYR-218 AND PHE-275.
[11]	"Downregulation of Fas ligand by shedding." Tanaka M., Itai T., Adachi M., Nagata S. Nat. Med. 4:31-36(1998) [PubMed: 9427603] [Abstract] Cited for: PROTEOLYTIC PROCESSING.
[12]	"Sorting of Fas ligand to secretory lysosomes is regulated by mono-ubiquitylation and phosphorylation." Zuccato E., Blott E.J., Holt O., Sigismund S., Shaw M., Bossi G., Griffiths G.M. J. Cell Sci. 120:191-199(2007) [PubMed: 17164290] [Abstract] Cited for: UBIQUITINATION, PHOSPHORYLATION, INTERACTION WITH FGR; FYN AND LYN, SUBCELLULAR LOCATION.
[13]	"Identification of SH3 domain interaction partners of human FasL (CD178) by phage display screening." Voss M., Lettau M., Janssen O. BMC Immunol. 10:53-53(2009) [PubMed: 19807924] [Abstract] Cited for: INTERACTION WITH ARHGAP9; BAIAP2L1; BTK; CACNB3; CACNB4; CRK; DLG2; DNMBP; DOCK4; EPS8L3; FYB; FYN; HCK; ITK; ITSN2; KALRN; LYN; MACC1; MIA; MPP4; MYO15A; NCF1; NCK1; NCK2; NCKIPSD; OSTF1; PIK3R1; PSTPIP1; RIMBP3C; SAMSN1; SH3GL3; SH3PXD2B; SH3PXD2A; SH3RF2; SKAP2; SNX33; SNX9; SORBS3; SPTA1; SRC; SRGAP1; SRGAP2; SRGAP3; TEC; TJP3 AND YES1.
+	Additional computationally mapped references.

Web resources

FASLGbase

FASLG mutation db

GeneReviews

Wikipedia

FAS-ligand entry

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U08137 mRNA. Translation: AAC50071.1.
U11821 mRNA. Translation: AAC50124.1.
X89102 mRNA. Translation: CAA61474.1.
D38122 mRNA. Translation: BAA07320.1.
AF288573 mRNA. Translation: AAG60017.1.
Z96050 Genomic DNA. Translation: CAB09424.1.
BC017502 mRNA. Translation: AAH17502.1.
AB013303 Genomic DNA. Translation: BAA32542.1.

IPI

IPI00007577.
IPI00220870.

PIR

I38707.

RefSeq

NP_000630.1. NM_000639.1.

UniGene

Hs.2007.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1BZI	model	-	B/C	1-281	[»]

ProteinModelPortal

P48023.

SMR

P48023. Positions 141-281.

ModBase

Search...

Protein-protein interaction databases

IntAct

P48023. 53 interactions.

MINT

MINT-238167.

STRING

P48023.

Polymorphism databases

DMDM

1345957.

Proteomic databases

PRIDE

P48023.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000367721; ENSP00000356694; ENSG00000117560.

GeneID

356.

KEGG

hsa:356.

UCSC

uc001gis.1. human.
uc001git.1. human.

Organism-specific databases

CTD

356.

GeneCards

GC01P172628.

H-InvDB

HIX0001337.

HGNC

HGNC:11936. FASLG.

HPA

CAB011435.

MIM

134638. gene.
601859. phenotype.

neXtProt

NX_P48023.

Orphanet

3261. Autoimmune lymphoproliferative syndrome.

PharmGKB

PA56.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG13732.

HOGENOM

HBG280463.

HOVERGEN

HBG055128.

InParanoid

P48023.

OMA

KQIGHPS.

OrthoDB

EOG469QVM.

PhylomeDB

P48023.

Enzyme and pathway databases

Pathway_Interaction_DB

nfat_tfpathway. Calcineurin-regulated NFAT-dependent transcription in lymphocytes.
tcrcalciumpathway. Calcium signaling in the CD4+ TCR pathway.
cd8tcrdownstreampathway. Downstream signaling in naive CD8+ T cells.
faspathway. FAS signaling pathway (CD95).
foxopathway. FoxO family signaling.
hivnefpathway. HIV-1 Nef: Negative effector of Fas and TNF-alpha.
il12_2pathway. IL12-mediated signaling events.
il2_stat5pathway. IL2 signaling events mediated by STAT5.

Reactome

REACT_578. Apoptosis.

Gene expression databases

ArrayExpress

P48023.

Bgee

P48023.

CleanEx

HS_FASLG.

Genevestigator

P48023.

GermOnline

ENSG00000117560. Homo sapiens.

Family and domain databases

InterPro

IPR008064. Fas_ligand.
IPR006052. TNF.
IPR006053. TNF_a/b/c.
IPR021184. TNF_CS.
IPR008983. Tumour_necrosis_fac-like.
[Graphical view]

Gene3D

G3DSA:2.60.120.40. Tumour_necrosis_fac-like. 1 hit.

KO

K04389.

PANTHER

PTHR11471:SF7. Fas_ligand. 1 hit.

Pfam

PF00229. TNF. 1 hit.
[Graphical view]

PRINTS

PR01681. FASLIGAND.
PR01234. TNECROSISFCT.

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

NextBio

1489.

PMAP-CutDB

P48023.

SOURCE

Search...

Entry information

Entry name

TNFL6_HUMAN

Accession

Primary (citable) accession number: P48023
Secondary accession number(s): Q9BZP9

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1996
Last sequence update:	February 1, 1996
Last modified:	January 25, 2012
This is version 135 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.