P41047 (TNFL6_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Tumor necrosis factor ligand superfamily member 6

Alternative name(s):
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:

1. Tumor necrosis factor ligand superfamily member 6, membrane form
2. Tumor necrosis factor ligand superfamily member 6, soluble form
   Alternative name(s):
   Receptor-binding FasL ectodomain
   Soluble Fas ligand
   Short name=sFasL
3. ADAM10-processed FasL form
   Short name=APL
4. FasL intracellular domain
   Short name=FasL ICD
   Alternative name(s):
   SPPL2A-processed FasL form
   Short name=SPA

Gene names

Name:	Faslg
Synonyms:	Apt1lg1, Cd95l, Fasl, gld, Tnfsf6

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	279 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 By similarity. The FasL intracellular domain (FasL ICD) cytoplasmic form induces gene transcription inhibition By similarity.
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 By similarity.
Subcellular location	Isoform FasL: Cell membrane; Single-pass type II membrane protein. Cytoplasmic vesicle lumen By similarity. Lysosome lumen By similarity. Note: Is internalized into multivesicular bodies of secretory lysosomes after phosphorylation by FGR and monoubiquitination. Colocalizes with the SPPL2A protease at the cell membrane By similarity. Isoform FasLS: Secreted. Tumor necrosis factor ligand superfamily member 6, soluble form: Secreted. Note: May be released into the extracellular fluid, probably by cleavage form the cell surface. FasL intracellular domain: Nucleus By similarity. Note: The FasL ICD cytoplasmic form is translocated into the nucleus By similarity.
Post-translational modification	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 By similarity. Phosphorylated by FGR on tyrosine residues; this is required for ubiquitination and subsequent internalization By similarity. N-glycosylated By similarity. Monoubiquitinated By similarity.
Involvement in disease	A deficiency in this protein is the cause of generalized lymphoproliferation disease phenotype (gld). Gld mice present lymphadenopathy and autoantibody production. The phenotype is recessively inherited.
Sequence similarities	Belongs to the tumor necrosis factor family.

Ontologies

Keywords
Biological process	Apoptosis Transcription Transcription regulation
Cellular component	Cell membrane Cytoplasmic vesicle Lysosome Membrane Nucleus Secreted
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Domain	Signal-anchor Transmembrane Transmembrane helix
Molecular function	Cytokine Repressor
PTM	Disulfide bond Glycoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	activation of cysteine-type endopeptidase activity involved in apoptotic process Inferred from electronic annotation. Source: Compara activation of necroptosis by extracellular signals Inferred from electronic annotation. Source: Compara activation of necroptosis of activated-T cells Inferred from electronic annotation. Source: Compara apoptotic signaling pathway Inferred from direct assay PubMed 15039234PubMed 15629131Ref.1. Source: MGI cellular chloride ion homeostasis Inferred from electronic annotation. Source: Compara cellular response to stress Inferred from electronic annotation. Source: Compara endosomal lumen acidification Inferred from electronic annotation. Source: Compara extrinsic apoptotic signaling pathway via death domain receptors Inferred from electronic annotation. Source: Compara immune response Inferred from electronic annotation. Source: InterPro inflammatory cell apoptotic process Inferred from electronic annotation. Source: Compara necrotic cell death Inferred from electronic annotation. Source: Compara negative regulation of angiogenesis Inferred from electronic annotation. Source: Compara negative regulation of transcription from RNA polymerase II promoter Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of I-kappaB kinase/NF-kappaB cascade Inferred from electronic annotation. Source: Compara positive regulation of apoptotic process Inferred from genetic interaction PubMed 15039234. Source: MGI positive regulation of cell proliferation Inferred from electronic annotation. Source: Compara positive regulation of epidermal growth factor receptor signaling pathway Inferred from electronic annotation. Source: Compara positive regulation of neuron apoptotic process Inferred from electronic annotation. Source: Compara response to growth factor stimulus Inferred from electronic annotation. Source: Compara response to lipopolysaccharide Inferred from electronic annotation. Source: Compara retinal cell programmed cell death Inferred from mutant phenotype PubMed 14517994. Source: MGI transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	caveola Inferred from electronic annotation. Source: Compara cytoplasmic membrane-bounded vesicle lumen Inferred from electronic annotation. Source: UniProtKB-SubCell external side of plasma membrane Inferred from direct assay PubMed 16973387. Source: MGI extracellular space Inferred from electronic annotation. Source: UniProtKB-KW integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW lysosomal lumen Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from sequence or structural similarity. Source: UniProtKB perinuclear region of cytoplasm Inferred from electronic annotation. Source: Compara
Complete GO annotation...

Alternative products

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

Isoform FasL (identifier: P41047-1)

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 FasLS (identifier: P41047-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-210: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 279	279	Tumor necrosis factor ligand superfamily member 6, membrane form		PRO_0000034508
	Chain	1 – 127	127	ADAM10-processed FasL form By similarity		PRO_0000417159
	Chain	1 – 80	80	FasL intracellular domain By similarity		PRO_0000417160
	Chain	128 – 279	152	Tumor necrosis factor ligand superfamily member 6, soluble form By similarity		PRO_0000034509
Regions
	Topological domain	1 – 78	78	Cytoplasmic Potential
	Transmembrane	79 – 100	22	Helical; Signal-anchor for type II membrane protein; Potential
	Topological domain	101 – 279	179	Extracellular Potential
	Compositional bias	4 – 69	66	Pro-rich
	Compositional bias	45 – 51	7	Poly-Pro
Sites
	Site	79 – 80	2	Cleavage; by SPPL2A By similarity
	Site	127 – 128	2	Cleavage; by ADAM10 By similarity
Amino acid modifications
	Glycosylation	117	1	N-linked (GlcNAc...) Potential
	Glycosylation	182	1	N-linked (GlcNAc...) Potential
	Glycosylation	248	1	N-linked (GlcNAc...) Potential
	Glycosylation	258	1	N-linked (GlcNAc...) Potential
	Disulfide bond	200 ↔ 231		Potential
Natural variations
	Alternative sequence	1 – 210	210	Missing in isoform FasLS.		VSP_006445
	Natural variant	184	1	T → A in strain: BALB/c, DBA/1 and DBA/2; enhances cytotoxicity. Ref.7
	Natural variant	218	1	E → G in strain: BALB/c, DBA/1 and DBA/2; enhances cytotoxicity. Ref.7
	Natural variant	273	1	F → L in gld; abolishes binding of FASL to its receptor.

Sequences

	Sequence		Length	Mass (Da)
	Isoform FasL [UniParc]. Last modified February 1, 1995. Version 1. Checksum: 37972E2728E0A1CA	FASTA	279	31,442
	10 20 30 40 50 60 MQQPMNYPCP QIFWVDSSAT SSWAPPGSVF PCPSCGPRGP DQRRPPPPPP PVSPLPPPSQ 70 80 90 100 110 120 PLPLPPLTPL KKKDHNTNLW LPVVFFMVLV ALVGMGLGMY QLFHLQKELA ELREFTNQSL 130 140 150 160 170 180 KVSSFEKQIA NPSTPSEKKE PRSVAHLTGN PHSRSIPLEW EDTYGTALIS GVKYKKGGLV 190 200 210 220 230 240 INETGLYFVY SKVYFRGQSC NNQPLNHKVY MRNSKYPEDL VLMEEKRLNY CTTGQIWAHS 250 260 270 SYLGAVFNLT SADHLYVNIS QLSLINFEES KTFFGLYKL
	Isoform FasLS [UniParc]. Checksum: 9BA6F24DD120A482	FASTA	69	8,040
	10 20 30 40 50 60 MRNSKYPEDL VLMEEKRLNY CTTGQIWAHS SYLGAVFNLT SADHLYVNIS QLSLINFEES KTFFGLYKL

References

[1]	"Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand." Takahashi T., Tanaka M., Brannan C.I., Jenkins N.A., Copeland N.G., Suda T., Nagata S. Cell 76:969-976(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM FASL).
[2]	"Comparative molecular modelling of the Fas-ligand and other members of the TNF family." Peitsch M.C., Tschopp J. Mol. Immunol. 32:761-772(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM FASL), 3D-STRUCTURE MODELING. Strain: C57BL/6.
[3]	"The mouse Fas-ligand gene is mutated in gld mice and is part of a TNF family gene cluster." Lynch D.H., Watson M.L., Alderson M.R., Baum P.R., Miller R.E., Tough T., Gibson M., Davis-Smith T., Smith C.A., Hunter K. Immunity 1:131-136(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM FASL).
[4]	"Mus musculus Balb/c Fas ligand differs from 129/SV Fas ligand in two amino acids." Fenner M.H., Shioda T., Isselbacher K.J. Submitted (MAY-1996) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM FASL). Strain: BALB/c.
[5]	"Cloning and expression of a short Fas ligand: a new alternatively spliced product of the mouse Fas ligand gene." Ayroldi E., D'Adamio F., Zollo O., Agostini M., Moraca R., Cannarile L., Migliorati G., Delfino D.V., Riccardi C. Blood 94:3456-3467(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM FASLS). Strain: C3H. Tissue: Spleen.
[6]	"Characterization of the non-functional Fas ligand of gld mice." Hahne M., Peitsch M.C., Irmler M., Schroeter M., Lowin B., Rousseau M., Bron C., Renno T., French L., Tschopp J. Int. Immunol. 7:1381-1386(1995) [PubMed] [Europe PMC] [Abstract] Cited for: CHARACTERIZATION OF VARIANT GLD.
[7]	"Polymorphism of murine Fas ligand that affects the biological activity." Kayagaki N., Yamaguchi N., Nagao F., Matsuo S., Maeda H., Okumura K., Yagita H. Proc. Natl. Acad. Sci. U.S.A. 94:3914-3919(1997) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS ALA-184 AND GLY-218. Strain: BALB/c, C3H, C57BL/6, DBA/1, DBA/2, MRL, NOD, NZB, NZW and SJL.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	U06948 mRNA. Translation: AAA17800.1. U10984 mRNA. Translation: AAA19778.1. S76752 mRNA. Translation: AAB33780.1. U58995 mRNA. Translation: AAB02915.1. AF119335 mRNA. Translation: AAD52106.1.
IPI	IPI00110272. IPI00227798.
PIR	A53062.
RefSeq	NP_034307.1. NM_010177.4.
UniGene	Mm.3355.
3D structure databases
ProteinModelPortal	P41047.
SMR	P41047. Positions 158-279.
ModBase	Search...
Protein-protein interaction databases
MINT	MINT-1486494.
Proteomic databases
PRIDE	P41047.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000000834; ENSMUSP00000000834; ENSMUSG00000000817.
GeneID	14103.
KEGG	mmu:14103.
Organism-specific databases
CTD	14103.
MGI	MGI:99255. Fasl.
Phylogenomic databases
eggNOG	NOG42315.
HOGENOM	HOG000290680.
HOVERGEN	HBG055128.
InParanoid	P41047.
KO	K04389.
OMA	KQIGHPS.
OrthoDB	EOG469QVM.
Gene expression databases
ArrayExpress	P41047.
Bgee	P41047.
CleanEx	MM_FASL.
Genevestigator	P41047.
GermOnline	ENSMUSG00000000817. Mus musculus.
Family and domain databases
Gene3D	2.60.120.40. 1 hit.
InterPro	IPR008064. Fas_ligand. IPR006052. TNF. IPR006053. TNF_a/b/c. IPR021184. TNF_CS. IPR008983. Tumour_necrosis_fac-like_dom. [Graphical view]
PANTHER	PTHR11471:SF7. PTHR11471:SF7. 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	285134.
PMAP-CutDB	P41047.
SOURCE	Search...

Entry information

Entry name

TNFL6_MOUSE

Accession

Primary (citable) accession number: P41047
Secondary accession number(s): Q61217, Q9R1F2

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1995
Last sequence update:	February 1, 1995
Last modified:	May 1, 2013
This is version 132 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program