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O89110 (CASP8_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 135. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Caspase-8

Short name=CASP-8
EC=3.4.22.61

Cleaved into the following 2 chains:

  1. Caspase-8 subunit p18
  2. Caspase-8 subunit p10
Gene names
Name:Casp8
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length480 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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 activity

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

Enzyme regulation

Probably negatively regulated by RFFL through proteasomal degradation By similarity. Inhibited by Z-VAD-FK, Crma and P35.

Subunit structure

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 By similarity. Interacts with TNFAIP8L2. Interacts with CASP8AP2. Ref.5 Ref.7

Tissue specificity

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 stage

In the embryo, highest expression occurs at day 7.

Post-translational modification

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.

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.

Sequence similarities

Belongs to the peptidase C14A family.

Contains 2 DED (death effector) domains.

Ontologies

Keywords
   Biological processApoptosis
   DomainRepeat
   Molecular functionHydrolase
Protease
Thiol protease
   PTMAcetylation
Phosphoprotein
Zymogen
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processactivation of cysteine-type endopeptidase activity involved in apoptotic process

Inferred from direct assay PubMed 12011074. Source: MGI

angiogenesis

Inferred from mutant phenotype PubMed 12404118. Source: MGI

apoptotic process

Inferred from direct assay PubMed 16183742. Source: MGI

apoptotic signaling pathway

Inferred from direct assay PubMed 16183742. Source: MGI

cardiac muscle tissue development

Traceable author statement PubMed 18309324. Source: UniProtKB

cellular response to mechanical stimulus

Inferred from electronic annotation. Source: Ensembl

cellular response to organic cyclic compound

Inferred from electronic annotation. Source: Ensembl

execution phase of apoptosis

Inferred from sequence or structural similarity. Source: UniProtKB

extrinsic apoptotic signaling pathway

Inferred from direct assay PubMed 10588860PubMed 12065591. Source: MGI

extrinsic apoptotic signaling pathway via death domain receptors

Inferred from mutant phenotype PubMed 15322156. Source: MGI

heart development

Inferred from mutant phenotype PubMed 12404118. Source: MGI

hepatocyte apoptotic process

Inferred from mutant phenotype PubMed 15322156. Source: MGI

macrophage differentiation

Traceable author statement PubMed 18309324. Source: UniProtKB

negative regulation of I-kappaB kinase/NF-kappaB signaling

Inferred from electronic annotation. Source: Ensembl

negative regulation of necroptotic process

Inferred from genetic interaction PubMed 21368763PubMed 21402742PubMed 22037414PubMed 22089168. Source: MGI

neural tube formation

Inferred from mutant phenotype PubMed 12404118. Source: MGI

positive regulation of I-kappaB kinase/NF-kappaB signaling

Inferred from electronic annotation. Source: Ensembl

positive regulation of extrinsic apoptotic signaling pathway

Inferred from genetic interaction PubMed 16183742. Source: MGI

positive regulation of macrophage differentiation

Inferred from electronic annotation. Source: Ensembl

positive regulation of proteolysis

Inferred from electronic annotation. Source: Ensembl

protein heterooligomerization

Inferred from electronic annotation. Source: Ensembl

proteolysis involved in cellular protein catabolic process

Inferred from electronic annotation. Source: Ensembl

regulation of apoptotic signaling pathway

Inferred from genetic interaction PubMed 15456877. Source: MGI

regulation of thymocyte apoptotic process

Inferred from genetic interaction PubMed 15456877. Source: MGI

response to antibiotic

Inferred from electronic annotation. Source: Ensembl

response to cobalt ion

Inferred from electronic annotation. Source: Ensembl

response to cold

Inferred from electronic annotation. Source: Ensembl

response to estradiol

Inferred from electronic annotation. Source: Ensembl

response to ethanol

Inferred from electronic annotation. Source: Ensembl

response to lipopolysaccharide

Inferred from electronic annotation. Source: Ensembl

response to tumor necrosis factor

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentCD95 death-inducing signaling complex

Inferred from electronic annotation. Source: Ensembl

Noc1p-Noc2p complex

Inferred from mutant phenotype PubMed 14657025. Source: MGI

cell body

Inferred from electronic annotation. Source: Ensembl

centrosome

Inferred from electronic annotation. Source: Ensembl

cytoplasm

Inferred from direct assay PubMed 12065591. Source: MGI

membrane raft

Inferred from electronic annotation. Source: Ensembl

mitochondrion

Inferred from direct assay PubMed 18614015. Source: MGI

neuron projection

Inferred from electronic annotation. Source: Ensembl

nucleus

Inferred from direct assay PubMed 12065591. Source: MGI

ripoptosome

Inferred from sequence or structural similarity. Source: UniProtKB

   Molecular_functioncysteine-type endopeptidase activity

Inferred from direct assay PubMed 15456877. Source: MGI

cysteine-type endopeptidase activity involved in apoptotic process

Inferred from direct assay PubMed 12065591PubMed 16183742. Source: MGI

death effector domain binding

Inferred from Biological aspect of Ancestor. Source: RefGenome

endopeptidase activity

Inferred from direct assay PubMed 22037414. Source: MGI

peptidase activity

Inferred from direct assay PubMed 11369777. Source: MGI

protein binding

Inferred from physical interaction PubMed 17159908PubMed 17170703Ref.7PubMed 21382479. Source: IntAct

protein heterodimerization activity

Inferred from physical interaction PubMed 21368763. Source: MGI

Complete GO annotation...

Binary interactions

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Propeptide1 – 218218 By similarity
PRO_0000004632
Chain219 – 376158Caspase-8 subunit p18
PRO_0000004633
Propeptide377 – 38711 By similarity
PRO_0000004634
Chain388 – 48093Caspase-8 subunit p10
PRO_0000004635

Regions

Domain3 – 8078DED 1
Domain101 – 17777DED 2

Sites

Active site3191 By similarity
Active site3621 By similarity

Amino acid modifications

Modified residue1881Phosphoserine Ref.6 Ref.8
Modified residue2131Phosphoserine Ref.6
Modified residue2261N6-acetyllysine Ref.9
Modified residue3361Phosphotyrosine By similarity
Modified residue3891Phosphoserine; by CDK1 By similarity

Experimental info

Sequence conflict68 – 714HISR → PHPVG in CAA04196. Ref.4
Sequence conflict94 – 996DNAQIS → RQCPRFL in CAA04196. Ref.4
Sequence conflict961A → V in CAA07677. Ref.2
Sequence conflict103 – 1075VMLFK → SCSFR in CAA04196. Ref.4
Sequence conflict4751K → N in CAA04196. Ref.4

Sequences

Sequence LengthMass (Da)Tools
O89110 [UniParc].

Last modified November 1, 1998. Version 1.
Checksum: 045268AE3DE5ED4F

FASTA48055,357
        10         20         30         40         50         60 
MDFQSCLYAI AEELGSEDLA ALKFLCLDYI PHKKQETIED AQKLFLRLRE KGMLEEGNLS 

        70         80         90        100        110        120 
FLKELLFHIS RWDLLVNFLD CNREEMVREL RDPDNAQISP YRVMLFKLSE EVSELELRSF 

       130        140        150        160        170        180 
KFLLNNEIPK CKLEDDLSLL EIFVEMEKRT MLAENNLETL KSICDQVNKS LLGKIEDYER 

       190        200        210        220        230        240 
SSTERRMSLE GREELPPSVL DEMSLKMAEL CDSPREQDSE SRTSDKVYQM KNKPRGYCLI 

       250        260        270        280        290        300 
INNHDFSKAR EDITQLRKMK DRKGTDCDKE ALSKTFKELH FEIVSYDDCT ANEIHEILEG 

       310        320        330        340        350        360 
YQSADHKNKD CFICCILSHG DKGVVYGTDG KEASIYDLTS YFTGSKCPSL SGKPKIFFIQ 

       370        380        390        400        410        420 
ACQGSNFQKG VPDEAGFEQQ NHTLEVDSSS HKNYIPDEAD FLLGMATVKN CVSYRDPVNG 

       430        440        450        460        470        480 
TWYIQSLCQS LRERCPQGDD ILSILTGVNY DVSNKDDRRN KGKQMPQPTF TLRKKLFFPP 

« Hide

References

« Hide 'large scale' references
[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]"Molecular cloning and identification of murine caspase-8."
Van de Craen M., Van Loo G., Declercq W., Schotte P., van den Brande I., Mandruzzato S., van der Bruggen P., Fiers W., Vandenabeele P.
J. Mol. Biol. 284:1017-1026(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], CHARACTERIZATION.
[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]"Large-scale phosphorylation analysis of mouse liver."
Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007) [PubMed] [Europe PMC] [Abstract]
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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF067841 expand/collapse EMBL AC list , 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.
CCDSCCDS14979.1.
RefSeqNP_001073595.1. NM_001080126.1.
NP_033942.1. NM_009812.2.
UniGeneMm.336851.

3D structure databases

ProteinModelPortalO89110.
SMRO89110. Positions 195-479.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid198500. 7 interactions.
DIPDIP-37435N.
IntActO89110. 7 interactions.
MINTMINT-91569.
STRING10090.ENSMUSP00000027189.

Protein family/group databases

MEROPSC14.009.

PTM databases

PhosphoSiteO89110.

Proteomic databases

MaxQBO89110.
PaxDbO89110.
PRIDEO89110.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000027189; ENSMUSP00000027189; ENSMUSG00000026029.
ENSMUST00000165549; ENSMUSP00000127375; ENSMUSG00000026029.
GeneID12370.
KEGGmmu:12370.
UCSCuc007bcs.1. mouse.

Organism-specific databases

CTD841.
MGIMGI:1261423. Casp8.

Phylogenomic databases

eggNOGNOG303276.
HOGENOMHOG000276884.
HOVERGENHBG050803.
InParanoidO89110.
KOK04398.
OMAIFIEMEK.
OrthoDBEOG7CRTQM.
PhylomeDBO89110.
TreeFamTF102023.

Enzyme and pathway databases

BRENDA3.4.22.61. 3474.

Gene expression databases

ArrayExpressO89110.
BgeeO89110.
CleanExMM_CASP8.
GenevestigatorO89110.

Family and domain databases

Gene3D1.10.533.10. 2 hits.
3.40.50.1460. 1 hit.
InterProIPR029030. 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]
PfamPF01335. DED. 2 hits.
PF00656. Peptidase_C14. 1 hit.
[Graphical view]
PRINTSPR00376. IL1BCENZYME.
SMARTSM00115. CASc. 1 hit.
SM00031. DED. 2 hits.
[Graphical view]
SUPFAMSSF47986. SSF47986. 2 hits.
PROSITEPS01122. 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]
ProtoNetSearch...

Other

NextBio281064.
PROO89110.
SOURCESearch...

Entry information

Entry nameCASP8_MOUSE
AccessionPrimary (citable) accession number: O89110
Secondary accession number(s): O35669
Entry history
Integrated into UniProtKB/Swiss-Prot: November 15, 2002
Last sequence update: November 1, 1998
Last modified: July 9, 2014
This is version 135 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Peptidase families

Classification of peptidase families and list of entries

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot