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O89110

- CASP8_MOUSE

UniProt

O89110 - CASP8_MOUSE

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Protein

Caspase-8

Gene

Casp8

Organism
Mus musculus (Mouse)
Status
Reviewed - 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

  1. cysteine-type endopeptidase activity Source: MGI
  2. cysteine-type endopeptidase activity involved in apoptotic process Source: MGI
  3. cysteine-type endopeptidase activity involved in apoptotic signaling pathway Source: Ensembl
  4. death effector domain binding Source: RefGenome
  5. endopeptidase activity Source: MGI
  6. peptidase activity Source: MGI
  7. protein heterodimerization activity Source: MGI

GO - Biological processi

  1. activation of cysteine-type endopeptidase activity involved in apoptotic process Source: MGI
  2. angiogenesis Source: MGI
  3. apoptotic process Source: MGI
  4. apoptotic signaling pathway Source: MGI
  5. cardiac muscle tissue development Source: UniProtKB
  6. cellular response to mechanical stimulus Source: Ensembl
  7. cellular response to organic cyclic compound Source: Ensembl
  8. execution phase of apoptosis Source: UniProtKB
  9. extrinsic apoptotic signaling pathway Source: MGI
  10. extrinsic apoptotic signaling pathway via death domain receptors Source: MGI
  11. heart development Source: MGI
  12. hepatocyte apoptotic process Source: MGI
  13. macrophage differentiation Source: UniProtKB
  14. negative regulation of I-kappaB kinase/NF-kappaB signaling Source: Ensembl
  15. negative regulation of necroptotic process Source: MGI
  16. neural tube formation Source: MGI
  17. positive regulation of extrinsic apoptotic signaling pathway Source: MGI
  18. positive regulation of I-kappaB kinase/NF-kappaB signaling Source: Ensembl
  19. positive regulation of macrophage differentiation Source: Ensembl
  20. positive regulation of proteolysis Source: Ensembl
  21. protein heterooligomerization Source: Ensembl
  22. proteolysis involved in cellular protein catabolic process Source: Ensembl
  23. regulation of apoptotic signaling pathway Source: MGI
  24. regulation of thymocyte apoptotic process Source: MGI
  25. response to antibiotic Source: Ensembl
  26. response to cobalt ion Source: Ensembl
  27. response to cold Source: Ensembl
  28. response to estradiol Source: Ensembl
  29. response to ethanol Source: Ensembl
  30. response to lipopolysaccharide Source: Ensembl
  31. response to tumor necrosis factor Source: Ensembl
Complete GO annotation...

Keywords - Molecular functioni

Hydrolase, Protease, Thiol protease

Keywords - Biological processi

Apoptosis

Enzyme and pathway databases

BRENDAi3.4.22.61. 3474.
ReactomeiREACT_196636. TRIF-mediated programmed cell death.
REACT_205717. NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10.
REACT_207035. Apoptotic execution phase.
REACT_208000. Activation, myristolyation of BID and translocation to mitochondria.
REACT_210562. Caspase-mediated cleavage of cytoskeletal proteins.
REACT_211125. NOD1/2 Signaling Pathway.
REACT_215122. Regulation by c-FLIP.
REACT_224460. Apoptotic cleavage of cellular proteins.
REACT_241657. Caspase-8 activation by cleavage.
REACT_243608. Dimerization of procaspase-8.
REACT_253999. TRAIL signaling.
REACT_263715. FasL/ CD95L signaling.

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: Chromosome 1

Organism-specific databases

MGIiMGI:1261423. Casp8.

Subcellular locationi

GO - Cellular componenti

  1. CD95 death-inducing signaling complex Source: Ensembl
  2. cell body Source: Ensembl
  3. cytoplasm Source: MGI
  4. membrane raft Source: Ensembl
  5. microtubule organizing center Source: Ensembl
  6. mitochondrion Source: MGI
  7. neuron projection Source: Ensembl
  8. Noc1p-Noc2p complex Source: MGI
  9. nucleus Source: MGI
  10. ripoptosome Source: UniProtKB
Complete GO annotation...

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.
GenevestigatoriO89110.

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.By similarity2 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. 1 PublicationCurated
Sequence conflicti94 – 996DNAQIS → RQCPRFL in CAA04196. 1 PublicationCurated
Sequence conflicti96 – 961A → V in CAA07677. (PubMed:9837723)Curated
Sequence conflicti103 – 1075VMLFK → SCSFR in CAA04196. 1 PublicationCurated
Sequence conflicti475 – 4751K → N in CAA04196. 1 PublicationCurated

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 .
CCDSi CCDS14979.1.
RefSeqi NP_001073595.1. NM_001080126.1.
NP_033942.1. NM_009812.2.
UniGenei Mm.336851.

3D structure databases

ProteinModelPortali O89110.
SMRi O89110. Positions 195-479.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 198500. 7 interactions.
DIPi DIP-37435N.
IntActi O89110. 7 interactions.
MINTi MINT-91569.
STRINGi 10090.ENSMUSP00000027189.

Protein family/group databases

MEROPSi C14.009.

PTM databases

PhosphoSitei O89110.

Proteomic databases

MaxQBi O89110.
PaxDbi O89110.
PRIDEi O89110.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSMUST00000027189 ; ENSMUSP00000027189 ; ENSMUSG00000026029 .
ENSMUST00000165549 ; ENSMUSP00000127375 ; ENSMUSG00000026029 .
GeneIDi 12370.
KEGGi mmu:12370.
UCSCi uc007bcs.1. mouse.

Organism-specific databases

CTDi 841.
MGIi MGI:1261423. Casp8.

Phylogenomic databases

eggNOGi NOG303276.
HOGENOMi HOG000276884.
HOVERGENi HBG050803.
InParanoidi O89110.
KOi K04398.
OMAi IFIEMEK.
OrthoDBi EOG7CRTQM.
PhylomeDBi O89110.
TreeFami TF102023.

Enzyme and pathway databases

BRENDAi 3.4.22.61. 3474.
Reactomei REACT_196636. TRIF-mediated programmed cell death.
REACT_205717. NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10.
REACT_207035. Apoptotic execution phase.
REACT_208000. Activation, myristolyation of BID and translocation to mitochondria.
REACT_210562. Caspase-mediated cleavage of cytoskeletal proteins.
REACT_211125. NOD1/2 Signaling Pathway.
REACT_215122. Regulation by c-FLIP.
REACT_224460. Apoptotic cleavage of cellular proteins.
REACT_241657. Caspase-8 activation by cleavage.
REACT_243608. Dimerization of procaspase-8.
REACT_253999. TRAIL signaling.
REACT_263715. FasL/ CD95L signaling.

Miscellaneous databases

NextBioi 281064.
PROi O89110.
SOURCEi Search...

Gene expression databases

Bgeei O89110.
CleanExi MM_CASP8.
ExpressionAtlasi O89110. baseline and differential.
Genevestigatori O89110.

Family and domain databases

Gene3Di 1.10.533.10. 2 hits.
3.40.50.1460. 1 hit.
InterProi IPR029030. 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 ]
Pfami PF01335. DED. 2 hits.
PF00656. Peptidase_C14. 1 hit.
[Graphical view ]
PRINTSi PR00376. IL1BCENZYME.
SMARTi SM00115. CASc. 1 hit.
SM00031. DED. 2 hits.
[Graphical view ]
SUPFAMi SSF47986. SSF47986. 2 hits.
PROSITEi PS01122. 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 ]
ProtoNeti Search...

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. "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.
  6. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-188 AND SER-213, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Liver.
  7. "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.
  8. "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.
  9. "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: November 26, 2014
This is version 139 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