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Protein

Tumor necrosis factor ligand superfamily member 6

Gene

FASLG

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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.1 Publication
The FasL intracellular domain (FasL ICD) cytoplasmic form induces gene transcription inhibition.1 Publication

GO - Molecular functioni

  • receptor binding Source: ProtInc

GO - Biological processi

Keywordsi

Molecular functionCytokine, Repressor
Biological processApoptosis, Transcription, Transcription regulation

Enzyme and pathway databases

ReactomeiR-HSA-140534. Ligand-dependent caspase activation.
R-HSA-3371378. Regulation by c-FLIP.
R-HSA-5213460. RIPK1-mediated regulated necrosis.
R-HSA-5218900. CASP8 activity is inhibited.
R-HSA-6785807. Interleukin-4 and 13 signaling.
R-HSA-69416. Dimerization of procaspase-8.
R-HSA-75157. FasL/ CD95L signaling.
R-HSA-8862803. Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models.
SIGNORiP48023.

Names & Taxonomyi

Protein namesi
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
Short name:
FasL
CD_antigen: CD178
Cleaved into the following 4 chains:
Alternative name(s):
Receptor-binding FasL ectodomain
Soluble Fas ligand
Short name:
sFasL
FasL intracellular domain
Short name:
FasL ICD
Alternative name(s):
SPPL2A-processed FasL form
Short name:
SPA
Gene namesi
Name:FASLG
Synonyms:APT1LG1, CD95L, FASL, TNFSF6
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

HGNCiHGNC:11936. FASLG.

Subcellular locationi

Tumor necrosis factor ligand superfamily member 6, soluble form :
  • Secreted By similarity

  • Note: May be released into the extracellular fluid, probably by cleavage form the cell surface.By similarity
FasL intracellular domain :
  • Nucleus

  • Note: The FasL ICD cytoplasmic form is translocated into the nucleus.

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 80CytoplasmicSequence analysisAdd BLAST80
Transmembranei81 – 102Helical; Signal-anchor for type II membrane proteinSequence analysisAdd BLAST22
Topological domaini103 – 281ExtracellularSequence analysisAdd BLAST179

GO - Cellular componenti

  • caveola Source: Ensembl
  • cytoplasmic vesicle lumen Source: UniProtKB-SubCell
  • external side of plasma membrane Source: Ensembl
  • extracellular exosome Source: UniProtKB
  • extracellular region Source: Reactome
  • extracellular space Source: BHF-UCL
  • integral component of plasma membrane Source: ProtInc
  • lysosomal lumen Source: UniProtKB-SubCell
  • nucleus Source: UniProtKB
  • perinuclear region of cytoplasm Source: Ensembl
  • plasma membrane Source: AgBase

Keywords - Cellular componenti

Cell membrane, Cytoplasmic vesicle, Lysosome, Membrane, Nucleus, Secreted

Pathology & Biotechi

Involvement in diseasei

Autoimmune lymphoproliferative syndrome 1B (ALPS1B)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA disorder of apoptosis that manifests in early childhood and results in the accumulation of autoreactive lymphocytes. It is characterized by non-malignant lymphadenopathy with hepatosplenomegaly, and autoimmune hemolytic anemia, thrombocytopenia and neutropenia.
See also OMIM:601859
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_075568202C → S in ALPS1B; significant reduction in cytotoxicity and apoptosis and inhibition of the shedding of the soluble form. 1 Publication1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi206P → D, F or R: Lowers binding to TNFRSF6 and reduces cytotoxicity more than 100-fold. 1 Publication1
Mutagenesisi218Y → F or R: Lowers binding to TNFRSF6 and abolishes cytotoxicity. 1 Publication1
Mutagenesisi275F → L: Abolishes binding to TNRFSF6 and cytotoxicity. 1 Publication1

Organism-specific databases

DisGeNETi356.
MalaCardsiFASLG.
MIMi601859. phenotype.
OpenTargetsiENSG00000117560.
Orphaneti3261. Autoimmune lymphoproliferative syndrome.
PharmGKBiPA56.

Chemistry databases

ChEMBLiCHEMBL5714.

Polymorphism and mutation databases

BioMutaiFASLG.
DMDMi1345957.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000345001 – 281Tumor necrosis factor ligand superfamily member 6, membrane formAdd BLAST281
ChainiPRO_00004171521 – 129ADAM10-processed FasL formAdd BLAST129
ChainiPRO_00004168421 – 81FasL intracellular domainAdd BLAST81
ChainiPRO_0000034501130 – 281Tumor necrosis factor ligand superfamily member 6, soluble formAdd BLAST152

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi184N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi202 ↔ 233Sequence analysis
Glycosylationi250N-linked (GlcNAc...)Sequence analysis1
Glycosylationi260N-linked (GlcNAc...)Sequence analysis1

Post-translational modificationi

The soluble form derives from the membrane form by proteolytic processing. The membrane-bound form undergoes two successive intramembrane proteolytic cleavages. The first one is processed by ADAM10 producing an N-terminal fragment, which lacks the receptor-binding extracellular domain. This ADAM10-processed FasL (FasL APL) remnant form is still membrane anchored and further processed by SPPL2A that liberates the FasL intracellular domain (FasL ICD). FasL shedding by ADAM10 is a prerequisite for subsequent intramembrane cleavage by SPPL2A in T-cells.2 Publications
N-glycosylated.
Phosphorylated by FGR on tyrosine residues; this is required for ubiquitination and subsequent internalization.1 Publication
Monoubiquitinated.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei81 – 82Cleavage; by SPPL2ACurated2
Sitei129 – 130Cleavage; by ADAM10Curated2

Keywords - PTMi

Disulfide bond, Glycoprotein, Ubl conjugation

Proteomic databases

PaxDbiP48023.
PeptideAtlasiP48023.
PRIDEiP48023.

PTM databases

iPTMnetiP48023.
PhosphoSitePlusiP48023.
SwissPalmiP48023.

Miscellaneous databases

PMAP-CutDBiP48023.

Expressioni

Gene expression databases

BgeeiENSG00000117560.
CleanExiHS_FASLG.
ExpressionAtlasiP48023. baseline and differential.
GenevisibleiP48023. HS.

Organism-specific databases

HPAiHPA054959.

Interactioni

Subunit structurei

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.Curated2 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • receptor binding Source: ProtInc

Protein-protein interaction databases

BioGridi106852. 82 interactors.
DIPiDIP-2997N.
IntActiP48023. 78 interactors.
MINTiMINT-238167.
STRINGi9606.ENSP00000356694.

Structurei

Secondary structure

1281
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi137 – 142Combined sources6
Beta strandi146 – 151Combined sources6
Beta strandi157 – 159Combined sources3
Beta strandi165 – 168Combined sources4
Beta strandi170 – 177Combined sources8
Beta strandi180 – 182Combined sources3
Beta strandi187 – 201Combined sources15
Beta strandi207 – 214Combined sources8
Beta strandi218 – 220Combined sources3
Beta strandi222 – 229Combined sources8
Beta strandi239 – 251Combined sources13
Beta strandi256 – 262Combined sources7
Helixi264 – 266Combined sources3
Turni271 – 273Combined sources3
Beta strandi274 – 280Combined sources7

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1BZImodel-B/C1-281[»]
4MSVX-ray2.50A130-281[»]
5L19X-ray2.00A130-281[»]
5L36X-ray3.10A130-281[»]
ProteinModelPortaliP48023.
SMRiP48023.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi4 – 70Pro-richAdd BLAST67
Compositional biasi45 – 65Poly-ProAdd BLAST21

Sequence similaritiesi

Belongs to the tumor necrosis factor family.Curated

Keywords - Domaini

Signal-anchor, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiENOG410IHZF. Eukaryota.
ENOG4112D9R. LUCA.
GeneTreeiENSGT00530000062992.
HOGENOMiHOG000290680.
HOVERGENiHBG055128.
InParanoidiP48023.
KOiK04389.
OMAiWEDTYGI.
OrthoDBiEOG091G0MFC.
PhylomeDBiP48023.
TreeFamiTF332169.

Family and domain databases

Gene3Di2.60.120.40. 1 hit.
InterProiView protein in InterPro
IPR028326. FASL.
IPR006053. TNF.
IPR021184. TNF_CS.
IPR006052. TNF_dom.
IPR008983. Tumour_necrosis_fac-like_dom.
PfamiView protein in Pfam
PF00229. TNF. 1 hit.
PRINTSiPR01681. FASLIGAND.
PR01234. TNECROSISFCT.
SMARTiView protein in SMART
SM00207. TNF. 1 hit.
SUPFAMiSSF49842. SSF49842. 1 hit.
PROSITEiView protein in PROSITE
PS00251. TNF_1. 1 hit.
PS50049. TNF_2. 1 hit.

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P48023-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MQQPFNYPYP QIYWVDSSAS SPWAPPGTVL PCPTSVPRRP GQRRPPPPPP
60 70 80 90 100
PPPLPPPPPP PPLPPLPLPP LKKRGNHSTG LCLLVMFFMV LVALVGLGLG
110 120 130 140 150
MFQLFHLQKE LAELRESTSQ MHTASSLEKQ IGHPSPPPEK KELRKVAHLT
160 170 180 190 200
GKSNSRSMPL EWEDTYGIVL LSGVKYKKGG LVINETGLYF VYSKVYFRGQ
210 220 230 240 250
SCNNLPLSHK VYMRNSKYPQ DLVMMEGKMM SYCTTGQMWA RSSYLGAVFN
260 270 280
LTSADHLYVN VSELSLVNFE ESQTFFGLYK L
Length:281
Mass (Da):31,485
Last modified:February 1, 1996 - v1
Checksum:iA8A6EB358246E9BB
GO
Isoform 2 (identifier: P48023-2) [UniParc]FASTAAdd to basket

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

Show »
Length:127
Mass (Da):14,006
Checksum:iF617D96B26B8E3BA
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_052583189Y → S. Corresponds to variant dbSNP:rs12079514Ensembl.1
Natural variantiVAR_075568202C → S in ALPS1B; significant reduction in cytotoxicity and apoptosis and inhibition of the shedding of the soluble form. 1 Publication1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_006443117 – 127STSQMHTASSL → ATPVHPLKKRS in isoform 2. 1 PublicationAdd BLAST11
Alternative sequenceiVSP_006444128 – 281Missing in isoform 2. 1 PublicationAdd BLAST154

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS1304.1. [P48023-1]
CCDS76243.1. [P48023-2]
PIRiI38707.
RefSeqiNP_000630.1. NM_000639.2. [P48023-1]
NP_001289675.1. NM_001302746.1. [P48023-2]
UniGeneiHs.2007.

Genome annotation databases

EnsembliENST00000340030; ENSP00000344739; ENSG00000117560. [P48023-2]
ENST00000367721; ENSP00000356694; ENSG00000117560. [P48023-1]
GeneIDi356.
KEGGihsa:356.
UCSCiuc001git.4. human. [P48023-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Web resourcesi

FASLGbase

FASLG mutation db

Wikipedia

FAS-ligand entry

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS1304.1. [P48023-1]
CCDS76243.1. [P48023-2]
PIRiI38707.
RefSeqiNP_000630.1. NM_000639.2. [P48023-1]
NP_001289675.1. NM_001302746.1. [P48023-2]
UniGeneiHs.2007.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1BZImodel-B/C1-281[»]
4MSVX-ray2.50A130-281[»]
5L19X-ray2.00A130-281[»]
5L36X-ray3.10A130-281[»]
ProteinModelPortaliP48023.
SMRiP48023.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi106852. 82 interactors.
DIPiDIP-2997N.
IntActiP48023. 78 interactors.
MINTiMINT-238167.
STRINGi9606.ENSP00000356694.

Chemistry databases

ChEMBLiCHEMBL5714.

PTM databases

iPTMnetiP48023.
PhosphoSitePlusiP48023.
SwissPalmiP48023.

Polymorphism and mutation databases

BioMutaiFASLG.
DMDMi1345957.

Proteomic databases

PaxDbiP48023.
PeptideAtlasiP48023.
PRIDEiP48023.

Protocols and materials databases

DNASUi356.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000340030; ENSP00000344739; ENSG00000117560. [P48023-2]
ENST00000367721; ENSP00000356694; ENSG00000117560. [P48023-1]
GeneIDi356.
KEGGihsa:356.
UCSCiuc001git.4. human. [P48023-1]

Organism-specific databases

CTDi356.
DisGeNETi356.
GeneCardsiFASLG.
GeneReviewsiFASLG.
HGNCiHGNC:11936. FASLG.
HPAiHPA054959.
MalaCardsiFASLG.
MIMi134638. gene.
601859. phenotype.
neXtProtiNX_P48023.
OpenTargetsiENSG00000117560.
Orphaneti3261. Autoimmune lymphoproliferative syndrome.
PharmGKBiPA56.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410IHZF. Eukaryota.
ENOG4112D9R. LUCA.
GeneTreeiENSGT00530000062992.
HOGENOMiHOG000290680.
HOVERGENiHBG055128.
InParanoidiP48023.
KOiK04389.
OMAiWEDTYGI.
OrthoDBiEOG091G0MFC.
PhylomeDBiP48023.
TreeFamiTF332169.

Enzyme and pathway databases

ReactomeiR-HSA-140534. Ligand-dependent caspase activation.
R-HSA-3371378. Regulation by c-FLIP.
R-HSA-5213460. RIPK1-mediated regulated necrosis.
R-HSA-5218900. CASP8 activity is inhibited.
R-HSA-6785807. Interleukin-4 and 13 signaling.
R-HSA-69416. Dimerization of procaspase-8.
R-HSA-75157. FasL/ CD95L signaling.
R-HSA-8862803. Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models.
SIGNORiP48023.

Miscellaneous databases

GeneWikiiFas_ligand.
GenomeRNAii356.
PMAP-CutDBiP48023.
PROiPR:P48023.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000117560.
CleanExiHS_FASLG.
ExpressionAtlasiP48023. baseline and differential.
GenevisibleiP48023. HS.

Family and domain databases

Gene3Di2.60.120.40. 1 hit.
InterProiView protein in InterPro
IPR028326. FASL.
IPR006053. TNF.
IPR021184. TNF_CS.
IPR006052. TNF_dom.
IPR008983. Tumour_necrosis_fac-like_dom.
PfamiView protein in Pfam
PF00229. TNF. 1 hit.
PRINTSiPR01681. FASLIGAND.
PR01234. TNECROSISFCT.
SMARTiView protein in SMART
SM00207. TNF. 1 hit.
SUPFAMiSSF49842. SSF49842. 1 hit.
PROSITEiView protein in PROSITE
PS00251. TNF_1. 1 hit.
PS50049. TNF_2. 1 hit.
ProtoNetiSearch...

Entry informationi

Entry nameiTNFL6_HUMAN
AccessioniPrimary (citable) accession number: P48023
Secondary accession number(s): Q9BZP9
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1996
Last sequence update: February 1, 1996
Last modified: March 15, 2017
This is version 188 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human cell differentiation molecules
    CD nomenclature of surface proteins of human leucocytes and list of entries
  2. Human chromosome 1
    Human chromosome 1: entries, gene names and cross-references to MIM
  3. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  4. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  5. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  6. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  7. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.