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P48023 (TNFL6_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified January 25, 2012. Version 135. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended 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
Gene names
Name:FASLG
Synonyms:APT1LG1, CD95L, FASL, TNFSF6
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length281 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence 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 processApoptosis
   Cellular componentCell membrane
Cytoplasmic vesicle
Lysosome
Membrane
Secreted
   Coding sequence diversityAlternative splicing
Polymorphism
   DomainSignal-anchor
Transmembrane
Transmembrane helix
   Molecular functionCytokine
   PTMDisulfide bond
Glycoprotein
Ubl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological processactivation 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 componentcytoplasmic 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 functioncytokine activity

Inferred from electronic annotation. Source: UniProtKB-KW

Complete GO annotation...

Binary interactions

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 keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 281281Tumor necrosis factor ligand superfamily member 6, membrane form
PRO_0000034500
Chain130 – 281152Tumor necrosis factor ligand superfamily member 6, soluble form
PRO_0000034501

Regions

Topological domain1 – 8080Cytoplasmic Potential
Transmembrane81 – 10222Helical; Signal-anchor for type II membrane protein; Potential
Topological domain103 – 281179Extracellular Potential
Compositional bias4 – 7067Pro-rich
Compositional bias45 – 6521Poly-Pro

Sites

Site129 – 1302Cleavage

Amino acid modifications

Glycosylation1841N-linked (GlcNAc...) Potential
Glycosylation2501N-linked (GlcNAc...) Potential
Glycosylation2601N-linked (GlcNAc...) Potential
Disulfide bond202 ↔ 233 Potential

Natural variations

Alternative sequence117 – 12711STSQMHTASSL → ATPVHPLKKRS in isoform 2.
VSP_006443
Alternative sequence128 – 281154Missing in isoform 2.
VSP_006444
Natural variant1891Y → S.
Corresponds to variant rs12079514 [ dbSNP | Ensembl ].
VAR_052583

Experimental info

Mutagenesis2061P → D, F or R: Lowers binding to TNFRSF6 and reduces cytotoxicity more than 100-fold. Ref.10
Mutagenesis2181Y → F or R: Lowers binding to TNFRSF6 and abolishes cytotoxicity. Ref.10
Mutagenesis2751F → L: Abolishes binding to TNRFSF6 and cytotoxicity. Ref.10

Secondary structure

.......................... 281
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified February 1, 1996. Version 1.
Checksum: A8A6EB358246E9BB

FASTA28131,485
        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 

« Hide

Isoform 2 [UniParc].

Checksum: F617D96B26B8E3BA
Show »

FASTA12714,006

References

« Hide '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. expand/collapse author list , 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.
IPIIPI00007577.
IPI00220870.
PIRI38707.
RefSeqNP_000630.1. NM_000639.1.
UniGeneHs.2007.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1BZImodel-B/C1-281[»]
ProteinModelPortalP48023.
SMRP48023. Positions 141-281.
ModBaseSearch...

Protein-protein interaction databases

IntActP48023. 53 interactions.
MINTMINT-238167.
STRINGP48023.

Polymorphism databases

DMDM1345957.

Proteomic databases

PRIDEP48023.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000367721; ENSP00000356694; ENSG00000117560.
GeneID356.
KEGGhsa:356.
UCSCuc001gis.1. human.
uc001git.1. human.

Organism-specific databases

CTD356.
GeneCardsGC01P172628.
H-InvDBHIX0001337.
HGNCHGNC:11936. FASLG.
HPACAB011435.
MIM134638. gene.
601859. phenotype.
neXtProtNX_P48023.
Orphanet3261. Autoimmune lymphoproliferative syndrome.
PharmGKBPA56.
GenAtlasSearch...

Phylogenomic databases

eggNOGprNOG13732.
HOGENOMHBG280463.
HOVERGENHBG055128.
InParanoidP48023.
OMAKQIGHPS.
OrthoDBEOG469QVM.
PhylomeDBP48023.

Enzyme and pathway databases

Pathway_Interaction_DBnfat_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.
ReactomeREACT_578. Apoptosis.

Gene expression databases

ArrayExpressP48023.
BgeeP48023.
CleanExHS_FASLG.
GenevestigatorP48023.
GermOnlineENSG00000117560. Homo sapiens.

Family and domain databases

InterProIPR008064. Fas_ligand.
IPR006052. TNF.
IPR006053. TNF_a/b/c.
IPR021184. TNF_CS.
IPR008983. Tumour_necrosis_fac-like.
[Graphical view]
Gene3DG3DSA:2.60.120.40. Tumour_necrosis_fac-like. 1 hit.
KOK04389.
PANTHERPTHR11471:SF7. Fas_ligand. 1 hit.
PfamPF00229. TNF. 1 hit.
[Graphical view]
PRINTSPR01681. FASLIGAND.
PR01234. TNECROSISFCT.
SMARTSM00207. TNF. 1 hit.
[Graphical view]
SUPFAMSSF49842. TNF_like. 1 hit.
PROSITEPS00251. TNF_1. 1 hit.
PS50049. TNF_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio1489.
PMAP-CutDBP48023.
SOURCESearch...

Entry information

Entry nameTNFL6_HUMAN
AccessionPrimary (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 statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Relevant documents

Human cell differentiation molecules

CD nomenclature of surface proteins of human leucocytes and list of entries

Human chromosome 1

Human chromosome 1: entries, gene names and cross-references to MIM

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

SIMILARITY comments

Index of protein domains and families