TNFL6_HUMAN
ID TNFL6_HUMAN Reviewed; 281 AA.
AC P48023; Q9BZP9;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1996, sequence version 1.
DT 03-AUG-2022, entry version 225.
DE RecName: Full=Tumor necrosis factor ligand superfamily member 6;
DE AltName: Full=Apoptosis antigen ligand;
DE Short=APTL;
DE AltName: Full=CD95 ligand;
DE Short=CD95-L;
DE AltName: Full=Fas antigen ligand;
DE Short=Fas ligand;
DE Short=FasL;
DE AltName: CD_antigen=CD178;
DE Contains:
DE RecName: Full=Tumor necrosis factor ligand superfamily member 6, membrane form;
DE Contains:
DE RecName: Full=Tumor necrosis factor ligand superfamily member 6, soluble form;
DE AltName: Full=Receptor-binding FasL ectodomain;
DE AltName: Full=Soluble Fas ligand;
DE Short=sFasL;
DE Contains:
DE RecName: Full=ADAM10-processed FasL form;
DE Short=APL;
DE Contains:
DE RecName: Full=FasL intracellular domain;
DE Short=FasL ICD;
DE AltName: Full=SPPL2A-processed FasL form;
DE Short=SPA;
GN Name=FASLG; Synonyms=APT1LG1, CD95L, FASL, TNFSF6;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION.
RX PubMed=7528780; DOI=10.1084/jem.181.1.71;
RA Alderson M.;
RT "Fas ligand mediates activation-induced cell death in human T
RT lymphocytes.";
RL J. Exp. Med. 181:71-77(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=7826947; DOI=10.1093/intimm/6.10.1567;
RA Takahashi T., Tanaka M., Inazawa J., Abe T., Suda T., Nagata S.;
RT "Human Fas ligand: gene structure, chromosomal location and species
RT specificity.";
RL Int. Immunol. 6:1567-1574(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Schaetzlein C.E., Poehlmann R., Philippsen P., Eibel H.;
RL Submitted (JUN-1995) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=7980502; DOI=10.1006/bbrc.1994.2483;
RA Mita E., Hayashi N., Iio S., Takehara T., Hijioka T., Kasahara A.,
RA Fusamoto H., Kamada T.;
RT "Role of Fas ligand in apoptosis induced by hepatitis C virus infection.";
RL Biochem. Biophys. Res. Commun. 204:468-474(1994).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RC TISSUE=Leukocyte;
RA Zeytun A., Nagarkatti M., Nagarkatti P.S.;
RT "Isolation and characterization of a new naturally occurring variant of
RT human Fas ligand that is expressed only in membrane bound form.";
RL Submitted (JUL-2000) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Blood;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-10.
RC TISSUE=Blood;
RA Matsumura M., Nakanishi Y., Ohba Y.;
RL Submitted (APR-1998) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP INVOLVEMENT IN ALPS1B.
RX PubMed=8787672; DOI=10.1172/jci118892;
RA Wu J., Wilson J., He J., Xiang L., Schur P.H., Mountz J.D.;
RT "Fas ligand mutation in a patient with systemic lupus erythematosus and
RT lymphoproliferative disease.";
RL J. Clin. Invest. 98:1107-1113(1996).
RN [10]
RP CHARACTERIZATION, AND MUTAGENESIS OF PRO-206; TYR-218 AND PHE-275.
RX PubMed=9228058; DOI=10.1074/jbc.272.30.18827;
RA Schneider P., Bodmer J.-L., Holler N., Mattmann C., Scuderi P.,
RA Terskikh A., Peitsch M.C., Tschopp J.;
RT "Characterization of Fas (Apo-1, CD95)-Fas ligand interaction.";
RL J. Biol. Chem. 272:18827-18833(1997).
RN [11]
RP PROTEOLYTIC PROCESSING, FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=9427603; DOI=10.1038/nm0198-031;
RA Tanaka M., Itai T., Adachi M., Nagata S.;
RT "Downregulation of Fas ligand by shedding.";
RL Nat. Med. 4:31-36(1998).
RN [12]
RP FUNCTION OF FASL INTRACELLULAR DOMAIN, CLEAVAGE BY ADAM10 AND SPPL2A, AND
RP SUBCELLULAR LOCATION.
RX PubMed=17557115; DOI=10.1038/sj.cdd.4402175;
RA Kirkin V., Cahuzac N., Guardiola-Serrano F., Huault S., Luckerath K.,
RA Friedmann E., Novac N., Wels W.S., Martoglio B., Hueber A.O., Zornig M.;
RT "The Fas ligand intracellular domain is released by ADAM10 and SPPL2a
RT cleavage in T-cells.";
RL Cell Death Differ. 14:1678-1687(2007).
RN [13]
RP UBIQUITINATION, PHOSPHORYLATION, INTERACTION WITH FGR; FYN AND LYN, AND
RP SUBCELLULAR LOCATION.
RX PubMed=17164290; DOI=10.1242/jcs.03315;
RA Zuccato E., Blott E.J., Holt O., Sigismund S., Shaw M., Bossi G.,
RA Griffiths G.M.;
RT "Sorting of Fas ligand to secretory lysosomes is regulated by mono-
RT ubiquitylation and phosphorylation.";
RL J. Cell Sci. 120:191-199(2007).
RN [14]
RP INTERACTION WITH ARHGAP9; BAIAP2L1; BTK; CACNB3; CACNB4; CRK; DLG2; DNMBP;
RP DOCK4; EPS8L3; FYB1; FYN; HCK; ITK; ITSN2; KALRN; LYN; MACC1; MIA; MPP4;
RP MYO15A; NCF1; NCK1; NCK2; NCKIPSD; OSTF1; PIK3R1; PSTPIP1; RIMBP3C; SAMSN1;
RP SH3GL3; SH3PXD2B; SH3PXD2A; SH3RF2; SKAP2; SNX33; SNX9; SORBS3; SPTA1; SRC;
RP SRGAP1; SRGAP2; SRGAP3; TEC; TJP3 AND YES1.
RX PubMed=19807924; DOI=10.1186/1471-2172-10-53;
RA Voss M., Lettau M., Janssen O.;
RT "Identification of SH3 domain interaction partners of human FasL (CD178) by
RT phage display screening.";
RL BMC Immunol. 10:53-53(2009).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 130-281 IN COMPLEX WITH TNFRSF6B,
RP FUNCTION, SUBUNIT, GLYCOSYLATION, AND DISULFIDE BOND.
RX PubMed=27806260; DOI=10.1016/j.str.2016.09.009;
RA Liu W., Ramagopal U., Cheng H., Bonanno J.B., Toro R., Bhosle R., Zhan C.,
RA Almo S.C.;
RT "Crystal structure of the complex of human FasL and its decoy receptor
RT DcR3.";
RL Structure 24:2016-2023(2016).
RN [16]
RP VARIANT ALPS1B SER-202, AND CHARACTERIZATION OF VARIANT ALPS1B SER-202.
RX PubMed=26334989; DOI=10.1038/pr.2015.170;
RA Ruiz-Garcia R., Mora S., Lozano-Sanchez G., Martinez-Lostao L.,
RA Paz-Artal E., Ruiz-Contreras J., Anel A., Gonzalez-Granado L.I.,
RA Moreno-Perez D., Allende L.M.;
RT "Decreased activation-induced cell death by EBV-transformed B-cells from a
RT patient with autoimmune lymphoproliferative syndrome caused by a novel
RT FASLG mutation.";
RL Pediatr. Res. 78:603-608(2015).
CC -!- FUNCTION: Cytokine that binds to TNFRSF6/FAS, a receptor that
CC transduces the apoptotic signal into cells (PubMed:26334989,
CC PubMed:9228058). Involved in cytotoxic T-cell-mediated apoptosis,
CC natural killer cell-mediated apoptosis and in T-cell development
CC (PubMed:9228058, PubMed:7528780, PubMed:9427603). Initiates
CC fratricidal/suicidal activation-induced cell death (AICD) in antigen-
CC activated T-cells contributing to the termination of immune responses
CC (By similarity). TNFRSF6/FAS-mediated apoptosis has also a role in the
CC induction of peripheral tolerance (By similarity). Binds to
CC TNFRSF6B/DcR3, a decoy receptor that blocks apoptosis
CC (PubMed:27806260). {ECO:0000250|UniProtKB:P41047,
CC ECO:0000269|PubMed:17557115, ECO:0000269|PubMed:27806260,
CC ECO:0000269|PubMed:7528780, ECO:0000269|PubMed:9228058,
CC ECO:0000269|PubMed:9427603}.
CC -!- FUNCTION: [Tumor necrosis factor ligand superfamily member 6, soluble
CC form]: Induces FAS-mediated activation of NF-kappa-B, initiating non-
CC apoptotic signaling pathways (By similarity). Can induce apoptosis but
CC does not appear to be essential for this process (PubMed:27806260).
CC {ECO:0000250|UniProtKB:P41047, ECO:0000269|PubMed:27806260}.
CC -!- FUNCTION: [FasL intracellular domain]: Cytoplasmic form induces gene
CC transcription inhibition. {ECO:0000269|PubMed:17557115}.
CC -!- SUBUNIT: Homotrimer (PubMed:27806260). Interacts with ARHGAP9,
CC BAIAP2L1, BTK, CACNB3, CACNB4, CRK, DLG2, DNMBP, DOCK4, EPS8L3, FGR,
CC FYB1, FYN, HCK, ITK, ITSN2, KALRN, LYN, MACC1, MIA, MPP4, MYO15A, NCF1,
CC NCK1, NCK2, NCKIPSD, OSTF1, PIK3R1, PSTPIP1, RIMBP3C, SAMSN1, SH3GL3,
CC SH3PXD2B, SH3PXD2A, SH3RF2, SKAP2, SNX33, SNX9, SORBS3, SPTA1, SRC,
CC SRGAP1, SRGAP2, SRGAP3, TEC, TJP3 and YES1.
CC {ECO:0000269|PubMed:17164290, ECO:0000269|PubMed:19807924,
CC ECO:0000269|PubMed:27806260, ECO:0000305}.
CC -!- INTERACTION:
CC P48023; Q14790: CASP8; NbExp=5; IntAct=EBI-495538, EBI-78060;
CC P48023; A8MQ03: CYSRT1; NbExp=3; IntAct=EBI-495538, EBI-3867333;
CC P48023; Q16610: ECM1; NbExp=3; IntAct=EBI-495538, EBI-947964;
CC P48023; Q13158: FADD; NbExp=4; IntAct=EBI-495538, EBI-494804;
CC P48023; P25445: FAS; NbExp=4; IntAct=EBI-495538, EBI-494743;
CC P48023; Q96RU3: FNBP1; NbExp=4; IntAct=EBI-495538, EBI-1111248;
CC P48023; P06241: FYN; NbExp=2; IntAct=EBI-495538, EBI-515315;
CC P48023; Q8IYA8: IHO1; NbExp=3; IntAct=EBI-495538, EBI-8638439;
CC P48023; Q08881: ITK; NbExp=3; IntAct=EBI-495538, EBI-968552;
CC P48023; Q14525: KRT33B; NbExp=3; IntAct=EBI-495538, EBI-1049638;
CC P48023; Q6A162: KRT40; NbExp=3; IntAct=EBI-495538, EBI-10171697;
CC P48023; Q8IUC1: KRTAP11-1; NbExp=3; IntAct=EBI-495538, EBI-1052037;
CC P48023; P60328: KRTAP12-3; NbExp=3; IntAct=EBI-495538, EBI-11953334;
CC P48023; A0A0S2Z4D7: NCK1; NbExp=3; IntAct=EBI-495538, EBI-16429340;
CC P48023; P16333-1: NCK1; NbExp=4; IntAct=EBI-495538, EBI-15578122;
CC P48023; O43639: NCK2; NbExp=4; IntAct=EBI-495538, EBI-713635;
CC P48023; Q7Z3S9: NOTCH2NLA; NbExp=3; IntAct=EBI-495538, EBI-945833;
CC P48023; Q9BY11: PACSIN1; NbExp=4; IntAct=EBI-495538, EBI-721769;
CC P48023; Q9UNF0: PACSIN2; NbExp=4; IntAct=EBI-495538, EBI-742503;
CC P48023; Q9UKS6: PACSIN3; NbExp=4; IntAct=EBI-495538, EBI-77926;
CC P48023; P27986: PIK3R1; NbExp=2; IntAct=EBI-495538, EBI-79464;
CC P48023; O43586: PSTPIP1; NbExp=5; IntAct=EBI-495538, EBI-1050964;
CC P48023; O76081: RGS20; NbExp=3; IntAct=EBI-495538, EBI-1052678;
CC P48023; O76081-6: RGS20; NbExp=6; IntAct=EBI-495538, EBI-10178530;
CC P48023; Q15436: SEC23A; NbExp=3; IntAct=EBI-495538, EBI-81088;
CC P48023; Q8WV41: SNX33; NbExp=3; IntAct=EBI-495538, EBI-2481535;
CC P48023; Q9Y5X1: SNX9; NbExp=2; IntAct=EBI-495538, EBI-77848;
CC P48023; O75044: SRGAP2; NbExp=2; IntAct=EBI-495538, EBI-1051034;
CC P48023; Q63HR2: TNS2; NbExp=3; IntAct=EBI-495538, EBI-949753;
CC P48023; Q15642: TRIP10; NbExp=4; IntAct=EBI-495538, EBI-739936;
CC P48023; Q15654: TRIP6; NbExp=3; IntAct=EBI-495538, EBI-742327;
CC P48023; Q9DBG3: Ap2b1; Xeno; NbExp=2; IntAct=EBI-495538, EBI-775229;
CC P48023; Q91ZR2: Snx18; Xeno; NbExp=4; IntAct=EBI-495538, EBI-6879954;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:17557115,
CC ECO:0000269|PubMed:9427603}; Single-pass type II membrane protein
CC {ECO:0000255}. Cytoplasmic vesicle lumen {ECO:0000269|PubMed:17164290}.
CC Lysosome lumen {ECO:0000269|PubMed:17164290}. Note=Is internalized into
CC multivesicular bodies of secretory lysosomes after phosphorylation by
CC FGR and monoubiquitination (PubMed:17164290). Colocalizes with the
CC SPPL2A protease at the cell membrane (PubMed:17557115).
CC {ECO:0000269|PubMed:17164290, ECO:0000269|PubMed:17557115}.
CC -!- SUBCELLULAR LOCATION: [Tumor necrosis factor ligand superfamily member
CC 6, soluble form]: Secreted {ECO:0000269|PubMed:9427603}. Note=May be
CC released into the extracellular fluid by cleavage from the cell
CC surface. {ECO:0000269|PubMed:9427603}.
CC -!- SUBCELLULAR LOCATION: [FasL intracellular domain]: Nucleus
CC {ECO:0000269|PubMed:17557115}. Note=The FasL ICD cytoplasmic form is
CC translocated into the nucleus. {ECO:0000269|PubMed:17557115}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P48023-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P48023-2; Sequence=VSP_006443, VSP_006444;
CC -!- PTM: The soluble form derives from the membrane form by proteolytic
CC processing. The membrane-bound form undergoes two successive
CC intramembrane proteolytic cleavages. The first one is processed by
CC ADAM10 producing an N-terminal fragment, which lacks the receptor-
CC binding extracellular domain. This ADAM10-processed FasL (FasL APL)
CC remnant form is still membrane anchored and further processed by SPPL2A
CC that liberates the FasL intracellular domain (FasL ICD). FasL shedding
CC by ADAM10 is a prerequisite for subsequent intramembrane cleavage by
CC SPPL2A in T-cells. {ECO:0000269|PubMed:17557115,
CC ECO:0000269|PubMed:9427603}.
CC -!- PTM: N-glycosylated (PubMed:9228058). Glycosylation enhances apoptotic
CC activity (PubMed:27806260). {ECO:0000269|PubMed:27806260,
CC ECO:0000269|PubMed:9228058}.
CC -!- PTM: Phosphorylated by FGR on tyrosine residues; this is required for
CC ubiquitination and subsequent internalization.
CC {ECO:0000269|PubMed:17164290}.
CC -!- PTM: Monoubiquitinated. {ECO:0000269|PubMed:17164290}.
CC -!- DISEASE: Autoimmune lymphoproliferative syndrome 1B (ALPS1B)
CC [MIM:601859]: A disorder of apoptosis that manifests in early childhood
CC and results in the accumulation of autoreactive lymphocytes. It is
CC characterized by non-malignant lymphadenopathy with hepatosplenomegaly,
CC and autoimmune hemolytic anemia, thrombocytopenia and neutropenia.
CC {ECO:0000269|PubMed:26334989, ECO:0000269|PubMed:8787672}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the tumor necrosis factor family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=FASLGbase; Note=FASLG mutation db;
CC URL="http://structure.bmc.lu.se/idbase/FASLGbase/";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=FAS-ligand entry;
CC URL="https://en.wikipedia.org/wiki/FAS_ligand";
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DR EMBL; U08137; AAC50071.1; -; mRNA.
DR EMBL; U11821; AAC50124.1; -; mRNA.
DR EMBL; X89102; CAA61474.1; -; mRNA.
DR EMBL; D38122; BAA07320.1; -; mRNA.
DR EMBL; AF288573; AAG60017.1; -; mRNA.
DR EMBL; Z96050; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC017502; AAH17502.1; -; mRNA.
DR EMBL; AB013303; BAA32542.1; -; Genomic_DNA.
DR CCDS; CCDS1304.1; -. [P48023-1]
DR CCDS; CCDS76243.1; -. [P48023-2]
DR PIR; I38707; I38707.
DR RefSeq; NP_000630.1; NM_000639.2. [P48023-1]
DR RefSeq; NP_001289675.1; NM_001302746.1. [P48023-2]
DR PDB; 4MSV; X-ray; 2.50 A; A=130-281.
DR PDB; 5L19; X-ray; 2.00 A; A=130-281.
DR PDB; 5L36; X-ray; 3.10 A; A=130-281.
DR PDBsum; 4MSV; -.
DR PDBsum; 5L19; -.
DR PDBsum; 5L36; -.
DR AlphaFoldDB; P48023; -.
DR SMR; P48023; -.
DR BioGRID; 106852; 93.
DR DIP; DIP-2997N; -.
DR ELM; P48023; -.
DR IntAct; P48023; 83.
DR MINT; P48023; -.
DR STRING; 9606.ENSP00000356694; -.
DR BindingDB; P48023; -.
DR ChEMBL; CHEMBL5714; -.
DR TCDB; 8.A.177.1.1; the tumor necrosis factor ligand member 6 (tnfl6) family.
DR GlyGen; P48023; 3 sites.
DR iPTMnet; P48023; -.
DR PhosphoSitePlus; P48023; -.
DR SwissPalm; P48023; -.
DR BioMuta; FASLG; -.
DR DMDM; 1345957; -.
DR MassIVE; P48023; -.
DR PaxDb; P48023; -.
DR PeptideAtlas; P48023; -.
DR PRIDE; P48023; -.
DR ABCD; P48023; 4 sequenced antibodies.
DR Antibodypedia; 4418; 1329 antibodies from 46 providers.
DR DNASU; 356; -.
DR Ensembl; ENST00000340030.4; ENSP00000344739.3; ENSG00000117560.8. [P48023-2]
DR Ensembl; ENST00000367721.3; ENSP00000356694.2; ENSG00000117560.8. [P48023-1]
DR GeneID; 356; -.
DR KEGG; hsa:356; -.
DR MANE-Select; ENST00000367721.3; ENSP00000356694.2; NM_000639.3; NP_000630.1.
DR UCSC; uc001git.4; human. [P48023-1]
DR CTD; 356; -.
DR DisGeNET; 356; -.
DR GeneCards; FASLG; -.
DR GeneReviews; FASLG; -.
DR HGNC; HGNC:11936; FASLG.
DR HPA; ENSG00000117560; Tissue enhanced (lymphoid).
DR MalaCards; FASLG; -.
DR MIM; 134638; gene.
DR MIM; 601859; phenotype.
DR neXtProt; NX_P48023; -.
DR OpenTargets; ENSG00000117560; -.
DR Orphanet; 3261; Autoimmune lymphoproliferative syndrome.
DR PharmGKB; PA56; -.
DR VEuPathDB; HostDB:ENSG00000117560; -.
DR eggNOG; ENOG502S09I; Eukaryota.
DR GeneTree; ENSGT01050000244957; -.
DR HOGENOM; CLU_070352_2_0_1; -.
DR InParanoid; P48023; -.
DR OMA; YPQIFWV; -.
DR PhylomeDB; P48023; -.
DR TreeFam; TF332169; -.
DR PathwayCommons; P48023; -.
DR Reactome; R-HSA-140534; Caspase activation via Death Receptors in the presence of ligand.
DR Reactome; R-HSA-3371378; Regulation by c-FLIP.
DR Reactome; R-HSA-5213460; RIPK1-mediated regulated necrosis.
DR Reactome; R-HSA-5218900; CASP8 activity is inhibited.
DR Reactome; R-HSA-6785807; Interleukin-4 and Interleukin-13 signaling.
DR Reactome; R-HSA-69416; Dimerization of procaspase-8.
DR Reactome; R-HSA-75157; FasL/ CD95L signaling.
DR Reactome; R-HSA-8862803; Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models.
DR Reactome; R-HSA-9614657; FOXO-mediated transcription of cell death genes.
DR SignaLink; P48023; -.
DR SIGNOR; P48023; -.
DR BioGRID-ORCS; 356; 9 hits in 1071 CRISPR screens.
DR ChiTaRS; FASLG; human.
DR GeneWiki; Fas_ligand; -.
DR GenomeRNAi; 356; -.
DR Pharos; P48023; Tbio.
DR PRO; PR:P48023; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; P48023; protein.
DR Bgee; ENSG00000117560; Expressed in granulocyte and 89 other tissues.
DR ExpressionAtlas; P48023; baseline and differential.
DR Genevisible; P48023; HS.
DR GO; GO:0005901; C:caveola; IEA:Ensembl.
DR GO; GO:0060205; C:cytoplasmic vesicle lumen; IEA:UniProtKB-SubCell.
DR GO; GO:0009897; C:external side of plasma membrane; IEA:Ensembl.
DR GO; GO:0070062; C:extracellular exosome; IDA:UniProtKB.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0005887; C:integral component of plasma membrane; TAS:ProtInc.
DR GO; GO:0043202; C:lysosomal lumen; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IDA:AgBase.
DR GO; GO:0005125; F:cytokine activity; IEA:UniProtKB-KW.
DR GO; GO:0005123; F:death receptor binding; IEA:Ensembl.
DR GO; GO:0005102; F:signaling receptor binding; TAS:ProtInc.
DR GO; GO:0005164; F:tumor necrosis factor receptor binding; IEA:Ensembl.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IMP:BHF-UCL.
DR GO; GO:0006915; P:apoptotic process; TAS:ProtInc.
DR GO; GO:0097190; P:apoptotic signaling pathway; IDA:BHF-UCL.
DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc.
DR GO; GO:0030644; P:cellular chloride ion homeostasis; IEA:Ensembl.
DR GO; GO:0071346; P:cellular response to interferon-gamma; IEA:Ensembl.
DR GO; GO:0048388; P:endosomal lumen acidification; IEA:Ensembl.
DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; IDA:UniProtKB.
DR GO; GO:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; IDA:BHF-UCL.
DR GO; GO:0006925; P:inflammatory cell apoptotic process; IEA:Ensembl.
DR GO; GO:0070266; P:necroptotic process; IDA:BHF-UCL.
DR GO; GO:0097527; P:necroptotic signaling pathway; IDA:BHF-UCL.
DR GO; GO:0016525; P:negative regulation of angiogenesis; IDA:BHF-UCL.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IEA:Ensembl.
DR GO; GO:2000353; P:positive regulation of endothelial cell apoptotic process; IDA:BHF-UCL.
DR GO; GO:0045742; P:positive regulation of epidermal growth factor receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IEP:UniProtKB.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:1905782; P:positive regulation of phosphatidylserine exposure on apoptotic cell surface; IDA:UniProtKB.
DR GO; GO:1903514; P:release of sequestered calcium ion into cytosol by endoplasmic reticulum; IDA:MGI.
DR GO; GO:0070848; P:response to growth factor; IEA:Ensembl.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0046666; P:retinal cell programmed cell death; IEA:Ensembl.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR GO; GO:0070231; P:T cell apoptotic process; IDA:UniProtKB.
DR CDD; cd00184; TNF; 1.
DR Gene3D; 2.60.120.40; -; 1.
DR InterPro; IPR028326; FASL.
DR InterPro; IPR006053; TNF.
DR InterPro; IPR021184; TNF_CS.
DR InterPro; IPR006052; TNF_dom.
DR InterPro; IPR008983; Tumour_necrosis_fac-like_dom.
DR Pfam; PF00229; TNF; 1.
DR PRINTS; PR01681; FASLIGAND.
DR PRINTS; PR01234; TNECROSISFCT.
DR SMART; SM00207; TNF; 1.
DR SUPFAM; SSF49842; SSF49842; 1.
DR PROSITE; PS00251; TNF_1; 1.
DR PROSITE; PS50049; TNF_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Apoptosis; Cell membrane; Cytokine;
KW Cytoplasmic vesicle; Disulfide bond; Glycoprotein; Lysosome; Membrane;
KW Nucleus; Reference proteome; Repressor; Secreted; Signal-anchor;
KW Transcription; Transcription regulation; Transmembrane;
KW Transmembrane helix; Ubl conjugation.
FT CHAIN 1..281
FT /note="Tumor necrosis factor ligand superfamily member 6,
FT membrane form"
FT /id="PRO_0000034500"
FT CHAIN 1..129
FT /note="ADAM10-processed FasL form"
FT /id="PRO_0000417152"
FT CHAIN 1..81
FT /note="FasL intracellular domain"
FT /id="PRO_0000416842"
FT CHAIN 130..281
FT /note="Tumor necrosis factor ligand superfamily member 6,
FT soluble form"
FT /id="PRO_0000034501"
FT TOPO_DOM 1..80
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 81..102
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 103..281
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT REGION 20..71
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 118..142
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 26..71
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 81..82
FT /note="Cleavage; by SPPL2A"
FT /evidence="ECO:0000305"
FT SITE 129..130
FT /note="Cleavage; by ADAM10"
FT /evidence="ECO:0000305"
FT CARBOHYD 184
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 250
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 260
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 202..233
FT /evidence="ECO:0000269|PubMed:27806260,
FT ECO:0007744|PDB:4MSV, ECO:0007744|PDB:5L19"
FT VAR_SEQ 117..127
FT /note="STSQMHTASSL -> ATPVHPLKKRS (in isoform 2)"
FT /evidence="ECO:0000303|Ref.5"
FT /id="VSP_006443"
FT VAR_SEQ 128..281
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|Ref.5"
FT /id="VSP_006444"
FT VARIANT 189
FT /note="Y -> S (in dbSNP:rs12079514)"
FT /id="VAR_052583"
FT VARIANT 202
FT /note="C -> S (in ALPS1B; significant reduction in
FT cytotoxicity and apoptosis and inhibition of the shedding
FT of the soluble form)"
FT /evidence="ECO:0000269|PubMed:26334989"
FT /id="VAR_075568"
FT MUTAGEN 206
FT /note="P->D,F,R: Lowers binding to TNFRSF6 and reduces
FT cytotoxicity more than 100-fold."
FT /evidence="ECO:0000269|PubMed:9228058"
FT MUTAGEN 218
FT /note="Y->F,R: Lowers binding to TNFRSF6 and abolishes
FT cytotoxicity."
FT /evidence="ECO:0000269|PubMed:9228058"
FT MUTAGEN 275
FT /note="F->L: Abolishes binding to TNRFSF6 and
FT cytotoxicity."
FT /evidence="ECO:0000269|PubMed:9228058"
FT HELIX 137..142
FT /evidence="ECO:0007829|PDB:5L19"
FT STRAND 146..151
FT /evidence="ECO:0007829|PDB:5L19"
FT STRAND 157..159
FT /evidence="ECO:0007829|PDB:4MSV"
FT STRAND 165..168
FT /evidence="ECO:0007829|PDB:4MSV"
FT STRAND 170..177
FT /evidence="ECO:0007829|PDB:5L19"
FT STRAND 180..182
FT /evidence="ECO:0007829|PDB:5L19"
FT STRAND 187..201
FT /evidence="ECO:0007829|PDB:5L19"
FT STRAND 207..214
FT /evidence="ECO:0007829|PDB:5L19"
FT STRAND 218..220
FT /evidence="ECO:0007829|PDB:4MSV"
FT STRAND 222..229
FT /evidence="ECO:0007829|PDB:5L19"
FT STRAND 239..251
FT /evidence="ECO:0007829|PDB:5L19"
FT STRAND 256..262
FT /evidence="ECO:0007829|PDB:5L19"
FT HELIX 264..266
FT /evidence="ECO:0007829|PDB:5L19"
FT TURN 271..273
FT /evidence="ECO:0007829|PDB:5L19"
FT STRAND 274..280
FT /evidence="ECO:0007829|PDB:5L19"
SQ SEQUENCE 281 AA; 31485 MW; A8A6EB358246E9BB CRC64;
MQQPFNYPYP QIYWVDSSAS SPWAPPGTVL PCPTSVPRRP GQRRPPPPPP PPPLPPPPPP
PPLPPLPLPP LKKRGNHSTG LCLLVMFFMV LVALVGLGLG MFQLFHLQKE LAELRESTSQ
MHTASSLEKQ IGHPSPPPEK KELRKVAHLT GKSNSRSMPL EWEDTYGIVL LSGVKYKKGG
LVINETGLYF VYSKVYFRGQ SCNNLPLSHK VYMRNSKYPQ DLVMMEGKMM SYCTTGQMWA
RSSYLGAVFN LTSADHLYVN VSELSLVNFE ESQTFFGLYK L
