Reviewed, UniProtKB/Swiss-Prot O89110 (CASP8_MOUSE)

Names and origin

Protein names

Recommended name:
    Caspase-8
      Short name=CASP-8
    EC=3.4.22.61
Cleaved into the following 2 chains:
    1- Recommended name:
            Caspase-8 subunit p18
    2- Recommended name:
            Caspase-8 subunit p10

Gene names

Name:

Casp8

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus

Protein attributes

Sequence length	480 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	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	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 By similarity. Interacts with TNFAIP8L2.
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. Phosphorylated upon DNA damage, probably by ATM or ATR By similarity.
Sequence similarities	Belongs to the peptidase C14A family. Contains 2 DED (death effector) domains.

Ontologies

Keywords
Biological process	Apoptosis
Domain	Repeat
Molecular function	Hydrolase Protease Thiol protease
PTM	Phosphoprotein Zymogen
Gene Ontology (GO)
Biological process	angiogenesis Inferred from mutant phenotype. Source: MGI apoptosis Inferred from direct assay. Source: MGI heart development Inferred from mutant phenotype. Source: MGI macrophage differentiation Inferred from mutant phenotype. Source: MGI neural tube formation Inferred from mutant phenotype. Source: MGI proteolysis Inferred from electronic annotation. Source: InterPro regulation of apoptosis Inferred from electronic annotation. Source: InterPro
Cellular component	Noc1p-Noc2p complex Inferred from mutant phenotype. Source: MGI mitochondrion Inferred from direct assay. Source: MGI
Molecular function	cysteine-type endopeptidase activity Inferred from electronic annotation. Source: InterPro protein binding Ref.5 Inferred from physical interaction. Source: IntAct
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Fadd	Q61160	1	EBI-851690,EBI-524415
Tnfaip8l2	Q9D8Y7	2	EBI-851690,EBI-1781612

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Propeptide	1 – 218	218	By similarity		PRO_0000004632
	Chain	219 – 376	158	Caspase-8 subunit p18		PRO_0000004633
	Propeptide	377 – 387	11	By similarity		PRO_0000004634
	Chain	388 – 480	93	Caspase-8 subunit p10		PRO_0000004635
Regions
	Domain	3 – 80	78	DED 1
	Domain	101 – 177	77	DED 2
Sites
	Active site	319	1	By similarity
	Active site	362	1	By similarity
Amino acid modifications
	Modified residue	188	1	Phosphoserine Ref.6 Ref.7 Ref.8
	Modified residue	221	1	Phosphoserine By similarity
	Modified residue	336	1	Phosphotyrosine By similarity
Experimental info
	Sequence conflict	68 – 71	4	HISR → PHPVG in CAA04196. Ref.4
	Sequence conflict	94 – 99	6	DNAQIS → RQCPRFL in CAA04196. Ref.4
	Sequence conflict	96	1	A → V in CAA07677. Ref.2
	Sequence conflict	103 – 107	5	VMLFK → SCSFR in CAA04196. Ref.4
	Sequence conflict	475	1	K → N in CAA04196. Ref.4

Sequences

	Sequence		Length	Mass (Da)
	O89110-1 [UniParc]. Last modified November 1, 1998. Version 1. Checksum: 045268AE3DE5ED4F	FASTA	480	55,357
	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

References

	« Hide 'large scale' referencesShow '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: 9654089] [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: 9837723] [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: 15489334] [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 OF 57-476.
[5]	"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: 18455983] [Abstract] Cited for: INTERACTION WITH TNFAIP8L2.
[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: 17242355] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-188, MASS SPECTROMETRY. Tissue: Liver.
[7]	"Specific phosphopeptide enrichment with immobilized titanium ion affinity chromatography adsorbent for phosphoproteome analysis." Zhou H., Ye M., Dong J., Han G., Jiang X., Wu R., Zou H. J. Proteome Res. 7:3957-3967(2008) [PubMed: 18630941] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-188, MASS SPECTROMETRY. Tissue: Liver.
[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: 19131326] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-188, MASS SPECTROMETRY.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBLGenBankDDBJ	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.
IPI	IPI00131533.
RefSeq	NP_001073595.1. NP_033942.1.
UniGene	Mm.336851
3D structure databases
HSSP	HSSP built from PDB template 1QTN based on UniProtKB Q9C0K4.
SMR	O89110. Positions 225-479.
ModBase	Search...
Protein-protein interaction databases
IntAct	O89110. 3 interactions.
STRING	O89110.
Protein family/group databases
MEROPS	C14.009.
PTM databases
PhosphoSite	O89110.
Proteomic databases
PRIDE	O89110.
Genome annotation databases
Ensembl	ENSMUST00000027189; ENSMUSP00000027189; ENSMUSG00000026029; Mus musculus. [Genome view]
GeneID	12370.
KEGG	mmu:12370.
UCSC	uc007bcs.1. mouse.
Organism-specific databases
CTD	12370.
MGI	MGI:1261423. Casp8.
Phylogenomic databases
HOGENOM	O89110.
HOVERGEN	O89110.
OMA	MGKQMPQ.
Enzyme and pathway databases
BRENDA	3.4.22.61. 244.
Gene expression databases
ArrayExpress	O89110.
Bgee	O89110.
CleanEx	MM_CASP8.
Genevestigator	O89110.
GermOnline	ENSMUSG00000026029. Mus musculus.
Family and domain databases
InterPro	IPR011029. DEATH-like. IPR001875. DED. IPR011600. Pept_C14_cat. IPR001309. Pept_C14_ICE_p20. IPR016129. Pept_C14_ICE_p20_AS. IPR002138. Pept_C14_p10. IPR002398. Pept_C14_p45. IPR015917. Pept_C14_p45_core. [Graphical view]
Gene3D	G3DSA:1.10.533.10. DEATH_like. 2 hits.
PANTHER	PTHR10454. Pept_C14_p45. 1 hit.
Pfam	PF01335. DED. 2 hits. PF00656. Peptidase_C14. 1 hit. [Graphical view]
PRINTS	PR00376. IL1BCENZYME.
SMART	SM00115. CASc. 1 hit. SM00031. DED. 2 hits. [Graphical view]
PROSITE	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]
ProtoNet	Search...
Other Resources
NextBio	281064.
SOURCE	Search...

Entry information

Entry name

CASP8_MOUSE

Accession

Primary (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:	November 3, 2009
This is version 91 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)