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Protein

Caspase-8

Gene

Casp8

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Most upstream protease of the activation cascade of caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death. Binding to the adapter molecule FADD recruits it to either receptor. The resulting aggregate called death-inducing signaling complex (DISC) performs CASP8 proteolytic activation. The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases. Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC. Cleaves and activates CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10. May participate in the GZMB apoptotic pathways. Cleaves ADPRT. Hydrolyzes the small-molecule substrate, Ac-Asp-Glu-Val-Asp-|-AMC. Likely target for the cowpox virus CRMA death inhibitory protein.

Catalytic activityi

Strict requirement for Asp at position P1 and has a preferred cleavage sequence of (Leu/Asp/Val)-Glu-Thr-Asp-|-(Gly/Ser/Ala).

Enzyme regulationi

Inhibited by CRMA and P35.1 Publication

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Active sitei319 – 3191By similarity
Active sitei362 – 3621By similarity

GO - Molecular functioni

  • cysteine-type endopeptidase activity Source: MGI
  • cysteine-type endopeptidase activity involved in apoptotic process Source: MGI
  • cysteine-type endopeptidase activity involved in apoptotic signaling pathway Source: MGI
  • death effector domain binding Source: MGI
  • endopeptidase activity Source: MGI
  • peptidase activity Source: MGI
  • protein heterodimerization activity Source: MGI
  • scaffold protein binding Source: MGI
  • ubiquitin protein ligase binding Source: MGI

GO - Biological processi

  • activation of cysteine-type endopeptidase activity Source: MGI
  • activation of cysteine-type endopeptidase activity involved in apoptotic process Source: MGI
  • angiogenesis Source: MGI
  • apoptotic process Source: MGI
  • apoptotic signaling pathway Source: MGI
  • cardiac muscle tissue development Source: UniProtKB
  • cellular response to mechanical stimulus Source: Ensembl
  • cellular response to organic cyclic compound Source: Ensembl
  • execution phase of apoptosis Source: UniProtKB
  • extrinsic apoptotic signaling pathway Source: MGI
  • extrinsic apoptotic signaling pathway via death domain receptors Source: MGI
  • heart development Source: MGI
  • hepatocyte apoptotic process Source: MGI
  • macrophage differentiation Source: UniProtKB
  • negative regulation of I-kappaB kinase/NF-kappaB signaling Source: MGI
  • negative regulation of necroptotic process Source: MGI
  • neural tube formation Source: MGI
  • positive regulation of extrinsic apoptotic signaling pathway Source: MGI
  • positive regulation of I-kappaB kinase/NF-kappaB signaling Source: MGI
  • positive regulation of macrophage differentiation Source: MGI
  • positive regulation of proteolysis Source: MGI
  • protein heterooligomerization Source: Ensembl
  • proteolysis Source: MGI
  • proteolysis involved in cellular protein catabolic process Source: MGI
  • regulation of apoptotic signaling pathway Source: MGI
  • regulation of thymocyte apoptotic process Source: MGI
  • response to antibiotic Source: Ensembl
  • response to cobalt ion Source: Ensembl
  • response to cold Source: Ensembl
  • response to estradiol Source: Ensembl
  • response to ethanol Source: Ensembl
  • response to lipopolysaccharide Source: Ensembl
  • response to tumor necrosis factor Source: MGI
  • TRAIL-activated apoptotic signaling pathway Source: MGI
Complete GO annotation...

Keywords - Molecular functioni

Hydrolase, Protease, Thiol protease

Keywords - Biological processi

Apoptosis

Enzyme and pathway databases

BRENDAi3.4.22.61. 3474.
ReactomeiREACT_277640. Apoptotic cleavage of cellular proteins.
REACT_284272. TRIF-mediated programmed cell death.
REACT_284952. FasL/ CD95L signaling.
REACT_286080. Apoptotic execution phase.
REACT_291081. Caspase-mediated cleavage of cytoskeletal proteins.
REACT_291404. TRAIL signaling.
REACT_301153. NOD1/2 Signaling Pathway.
REACT_301406. Dimerization of procaspase-8.
REACT_310781. Regulation by c-FLIP.
REACT_332213. NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10.
REACT_335353. Activation, myristolyation of BID and translocation to mitochondria.
REACT_354529. Ligand-dependent caspase activation.
REACT_357294. TNFR1-mediated proapoptotic signaling.
REACT_358772. CLEC7A/inflammasome pathway.
REACT_362347. CASP8 activity is inhibited.
REACT_362359. RIPK1-mediated regulated necrosis.

Protein family/group databases

MEROPSiC14.009.

Names & Taxonomyi

Protein namesi
Recommended name:
Caspase-8 (EC:3.4.22.61)
Short name:
CASP-8
Cleaved into the following 2 chains:
Gene namesi
Name:Casp8
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589 Componenti: Chromosome 1

Organism-specific databases

MGIiMGI:1261423. Casp8.

Subcellular locationi

GO - Cellular componenti

  • CD95 death-inducing signaling complex Source: MGI
  • cell body Source: Ensembl
  • cytoplasm Source: ParkinsonsUK-UCL
  • cytosol Source: MGI
  • death-inducing signaling complex Source: MGI
  • membrane raft Source: Ensembl
  • microtubule organizing center Source: MGI
  • mitochondrion Source: MGI
  • neuron projection Source: Ensembl
  • Noc1p-Noc2p complex Source: MGI
  • nucleoplasm Source: MGI
  • nucleus Source: MGI
  • plasma membrane Source: ParkinsonsUK-UCL
  • ripoptosome Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Propeptidei1 – 218218By similarityPRO_0000004632Add
BLAST
Chaini219 – 376158Caspase-8 subunit p18PRO_0000004633Add
BLAST
Propeptidei377 – 38711By similarityPRO_0000004634Add
BLAST
Chaini388 – 48093Caspase-8 subunit p10PRO_0000004635Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei188 – 1881Phosphoserine2 Publications
Modified residuei213 – 2131Phosphoserine1 Publication
Modified residuei226 – 2261N6-acetyllysine1 Publication
Modified residuei336 – 3361PhosphotyrosineBy similarity
Modified residuei389 – 3891Phosphoserine; by CDK1By similarity

Post-translational modificationi

Generation of the subunits requires association with the death-inducing signaling complex (DISC), whereas additional processing is likely due to the autocatalytic activity of the activated protease. GZMB and CASP10 can be involved in these processing events (By similarity).By similarity
Phosphorylation on Ser-389 during mitosis by CDK1 inhibits activation by proteolysis and prevents apoptosis. This phosphorylation occurs in cancer cell lines, as well as in primary breast tissues and lymphocytes (By similarity).By similarity

Keywords - PTMi

Acetylation, Phosphoprotein, Zymogen

Proteomic databases

MaxQBiO89110.
PaxDbiO89110.
PRIDEiO89110.

PTM databases

PhosphoSiteiO89110.

Expressioni

Tissue specificityi

Expressed in a wide variety of tissues. Highest expression in spleen, thymus, lung, liver and kidney. Lower expression in heart, brain, testis and skeletal muscle.

Developmental stagei

In the embryo, highest expression occurs at day 7.

Gene expression databases

BgeeiO89110.
CleanExiMM_CASP8.
ExpressionAtlasiO89110. baseline and differential.
GenevisibleiO89110. MM.

Interactioni

Subunit structurei

Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (p18) and a 10 kDa (p10) subunit. Interacts with FADD, CFLAR and PEA15. Interacts with RFFL and RNF34; negatively regulate CASP8 through proteasomal degradation (By similarity). Interacts with TNFAIP8L2. Interacts with CASP8AP2. Interacts with NOL3; decreases CASP8 activity in a mitochondria localization- and phosphorylation-dependent manner and this interaction is dissociated by calcium.By similarity3 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
ARP102752EBI-851690,EBI-608057From a different organism.
ArP190912EBI-851690,EBI-1776062
FasP254463EBI-851690,EBI-296206
Tnfaip8l2Q9D8Y72EBI-851690,EBI-1781612

Protein-protein interaction databases

BioGridi198500. 7 interactions.
DIPiDIP-37435N.
IntActiO89110. 7 interactions.
MINTiMINT-91569.
STRINGi10090.ENSMUSP00000027189.

Structurei

3D structure databases

ProteinModelPortaliO89110.
SMRiO89110. Positions 195-479.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini3 – 8078DED 1PROSITE-ProRule annotationAdd
BLAST
Domaini101 – 17777DED 2PROSITE-ProRule annotationAdd
BLAST

Sequence similaritiesi

Belongs to the peptidase C14A family.Curated
Contains 2 DED (death effector) domains.PROSITE-ProRule annotation

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiNOG303276.
HOGENOMiHOG000276884.
HOVERGENiHBG050803.
InParanoidiO89110.
KOiK04398.
OMAiIFIEMEK.
OrthoDBiEOG7CRTQM.
PhylomeDBiO89110.
TreeFamiTF102023.

Family and domain databases

Gene3Di1.10.533.10. 2 hits.
3.40.50.1460. 1 hit.
InterProiIPR029030. Caspase-like_dom.
IPR011029. DEATH-like_dom.
IPR001875. DED.
IPR011600. Pept_C14_caspase.
IPR001309. Pept_C14_ICE_p20.
IPR016129. Pept_C14_ICE_p20_AS.
IPR002138. Pept_C14_p10.
IPR015917. Pept_C14A_p45_core.
[Graphical view]
PfamiPF01335. DED. 2 hits.
PF00656. Peptidase_C14. 1 hit.
[Graphical view]
PRINTSiPR00376. IL1BCENZYME.
SMARTiSM00115. CASc. 1 hit.
SM00031. DED. 2 hits.
[Graphical view]
SUPFAMiSSF47986. SSF47986. 2 hits.
PROSITEiPS01122. CASPASE_CYS. 1 hit.
PS01121. CASPASE_HIS. 1 hit.
PS50207. CASPASE_P10. 1 hit.
PS50208. CASPASE_P20. 1 hit.
PS50168. DED. 2 hits.
[Graphical view]

Sequencei

Sequence statusi: Complete.

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

O89110-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MDFQSCLYAI AEELGSEDLA ALKFLCLDYI PHKKQETIED AQKLFLRLRE
60 70 80 90 100
KGMLEEGNLS FLKELLFHIS RWDLLVNFLD CNREEMVREL RDPDNAQISP
110 120 130 140 150
YRVMLFKLSE EVSELELRSF KFLLNNEIPK CKLEDDLSLL EIFVEMEKRT
160 170 180 190 200
MLAENNLETL KSICDQVNKS LLGKIEDYER SSTERRMSLE GREELPPSVL
210 220 230 240 250
DEMSLKMAEL CDSPREQDSE SRTSDKVYQM KNKPRGYCLI INNHDFSKAR
260 270 280 290 300
EDITQLRKMK DRKGTDCDKE ALSKTFKELH FEIVSYDDCT ANEIHEILEG
310 320 330 340 350
YQSADHKNKD CFICCILSHG DKGVVYGTDG KEASIYDLTS YFTGSKCPSL
360 370 380 390 400
SGKPKIFFIQ ACQGSNFQKG VPDEAGFEQQ NHTLEVDSSS HKNYIPDEAD
410 420 430 440 450
FLLGMATVKN CVSYRDPVNG TWYIQSLCQS LRERCPQGDD ILSILTGVNY
460 470 480
DVSNKDDRRN KGKQMPQPTF TLRKKLFFPP
Length:480
Mass (Da):55,357
Last modified:November 1, 1998 - v1
Checksum:i045268AE3DE5ED4F
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti68 – 714HISR → PHPVG in CAA04196 (Ref. 4) Curated
Sequence conflicti94 – 996DNAQIS → RQCPRFL in CAA04196 (Ref. 4) Curated
Sequence conflicti96 – 961A → V in CAA07677 (PubMed:9837723).Curated
Sequence conflicti103 – 1075VMLFK → SCSFR in CAA04196 (Ref. 4) Curated
Sequence conflicti475 – 4751K → N in CAA04196 (Ref. 4) Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF067841
, AF067835, AF067836, AF067837, AF067838, AF067839, AF067840 Genomic DNA. Translation: AAC40132.1.
AF067834 mRNA. Translation: AAC40131.1.
AJ007749 mRNA. Translation: CAA07677.1.
BC006737 mRNA. Translation: AAH06737.1.
BC049955 mRNA. Translation: AAH49955.1.
AJ000641 mRNA. Translation: CAA04196.1.
CCDSiCCDS14979.1.
RefSeqiNP_001073595.1. NM_001080126.1.
NP_033942.1. NM_009812.2.
UniGeneiMm.336851.

Genome annotation databases

EnsembliENSMUST00000027189; ENSMUSP00000027189; ENSMUSG00000026029.
ENSMUST00000165549; ENSMUSP00000127375; ENSMUSG00000026029.
GeneIDi12370.
KEGGimmu:12370.
UCSCiuc007bcs.1. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF067841
, AF067835, AF067836, AF067837, AF067838, AF067839, AF067840 Genomic DNA. Translation: AAC40132.1.
AF067834 mRNA. Translation: AAC40131.1.
AJ007749 mRNA. Translation: CAA07677.1.
BC006737 mRNA. Translation: AAH06737.1.
BC049955 mRNA. Translation: AAH49955.1.
AJ000641 mRNA. Translation: CAA04196.1.
CCDSiCCDS14979.1.
RefSeqiNP_001073595.1. NM_001080126.1.
NP_033942.1. NM_009812.2.
UniGeneiMm.336851.

3D structure databases

ProteinModelPortaliO89110.
SMRiO89110. Positions 195-479.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi198500. 7 interactions.
DIPiDIP-37435N.
IntActiO89110. 7 interactions.
MINTiMINT-91569.
STRINGi10090.ENSMUSP00000027189.

Protein family/group databases

MEROPSiC14.009.

PTM databases

PhosphoSiteiO89110.

Proteomic databases

MaxQBiO89110.
PaxDbiO89110.
PRIDEiO89110.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000027189; ENSMUSP00000027189; ENSMUSG00000026029.
ENSMUST00000165549; ENSMUSP00000127375; ENSMUSG00000026029.
GeneIDi12370.
KEGGimmu:12370.
UCSCiuc007bcs.1. mouse.

Organism-specific databases

CTDi841.
MGIiMGI:1261423. Casp8.

Phylogenomic databases

eggNOGiNOG303276.
HOGENOMiHOG000276884.
HOVERGENiHBG050803.
InParanoidiO89110.
KOiK04398.
OMAiIFIEMEK.
OrthoDBiEOG7CRTQM.
PhylomeDBiO89110.
TreeFamiTF102023.

Enzyme and pathway databases

BRENDAi3.4.22.61. 3474.
ReactomeiREACT_277640. Apoptotic cleavage of cellular proteins.
REACT_284272. TRIF-mediated programmed cell death.
REACT_284952. FasL/ CD95L signaling.
REACT_286080. Apoptotic execution phase.
REACT_291081. Caspase-mediated cleavage of cytoskeletal proteins.
REACT_291404. TRAIL signaling.
REACT_301153. NOD1/2 Signaling Pathway.
REACT_301406. Dimerization of procaspase-8.
REACT_310781. Regulation by c-FLIP.
REACT_332213. NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10.
REACT_335353. Activation, myristolyation of BID and translocation to mitochondria.
REACT_354529. Ligand-dependent caspase activation.
REACT_357294. TNFR1-mediated proapoptotic signaling.
REACT_358772. CLEC7A/inflammasome pathway.
REACT_362347. CASP8 activity is inhibited.
REACT_362359. RIPK1-mediated regulated necrosis.

Miscellaneous databases

NextBioi281064.
PROiO89110.
SOURCEiSearch...

Gene expression databases

BgeeiO89110.
CleanExiMM_CASP8.
ExpressionAtlasiO89110. baseline and differential.
GenevisibleiO89110. MM.

Family and domain databases

Gene3Di1.10.533.10. 2 hits.
3.40.50.1460. 1 hit.
InterProiIPR029030. Caspase-like_dom.
IPR011029. DEATH-like_dom.
IPR001875. DED.
IPR011600. Pept_C14_caspase.
IPR001309. Pept_C14_ICE_p20.
IPR016129. Pept_C14_ICE_p20_AS.
IPR002138. Pept_C14_p10.
IPR015917. Pept_C14A_p45_core.
[Graphical view]
PfamiPF01335. DED. 2 hits.
PF00656. Peptidase_C14. 1 hit.
[Graphical view]
PRINTSiPR00376. IL1BCENZYME.
SMARTiSM00115. CASc. 1 hit.
SM00031. DED. 2 hits.
[Graphical view]
SUPFAMiSSF47986. SSF47986. 2 hits.
PROSITEiPS01122. CASPASE_CYS. 1 hit.
PS01121. CASPASE_HIS. 1 hit.
PS50207. CASPASE_P10. 1 hit.
PS50208. CASPASE_P20. 1 hit.
PS50168. DED. 2 hits.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "Molecular cloning and characterization of mouse caspase-8."
    Sakamaki K., Tsukumo S., Yonehara S.
    Eur. J. Biochem. 253:399-405(1998) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], CHARACTERIZATION.
    Strain: 129/SvJ.
  2. Cited for: NUCLEOTIDE SEQUENCE [MRNA], CHARACTERIZATION, ENZYME REGULATION.
  3. "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] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Strain: FVB/N.
    Tissue: Colon and Mammary gland.
  4. Kioschis P., Kischkel F., Poustka A., Krammer P.
    Submitted (JUL-1997) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 57-476.
  5. "Inhibition of both the extrinsic and intrinsic death pathways through nonhomotypic death-fold interactions."
    Nam Y.J., Mani K., Ashton A.W., Peng C.F., Krishnamurthy B., Hayakawa Y., Lee P., Korsmeyer S.J., Kitsis R.N.
    Mol. Cell 15:901-912(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH NOL3.
  6. "FLASH links the CD95 signaling pathway to the cell nucleus and nuclear bodies."
    Milovic-Holm K., Krieghoff E., Jensen K., Will H., Hofmann T.G.
    EMBO J. 26:391-401(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH CASP8AP2.
  7. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-188 AND SER-213, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Liver.
  8. "TIPE2, a negative regulator of innate and adaptive immunity that maintains immune homeostasis."
    Sun H., Gong S., Carmody R.J., Hilliard A., Li L., Sun J., Kong L., Xu L., Hilliard B., Hu S., Shen H., Yang X., Chen Y.H.
    Cell 133:415-426(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH TNFAIP8L2.
  9. "Large scale localization of protein phosphorylation by use of electron capture dissociation mass spectrometry."
    Sweet S.M., Bailey C.M., Cunningham D.L., Heath J.K., Cooper H.J.
    Mol. Cell. Proteomics 8:904-912(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-188, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Embryonic fibroblast.
  10. "SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways."
    Park J., Chen Y., Tishkoff D.X., Peng C., Tan M., Dai L., Xie Z., Zhang Y., Zwaans B.M., Skinner M.E., Lombard D.B., Zhao Y.
    Mol. Cell 50:919-930(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-226, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Embryonic fibroblast.

Entry informationi

Entry nameiCASP8_MOUSE
AccessioniPrimary (citable) accession number: O89110
Secondary accession number(s): O35669
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 15, 2002
Last sequence update: November 1, 1998
Last modified: June 24, 2015
This is version 146 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Peptidase families
    Classification of peptidase families and list of entries
  3. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

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 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.