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Protein

Caspase-8

Gene

Casp8

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -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)DescriptionActionsGraphical viewLength
Active sitei319By similarity1
Active sitei362By similarity1

GO - Molecular functioni

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
  • 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: MGI
  • 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 apoptotic process 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
  • 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 tumor necrosis factor Source: MGI
  • TRAIL-activated apoptotic signaling pathway Source: MGI

Keywordsi

Molecular functionHydrolase, Protease, Thiol protease
Biological processApoptosis

Enzyme and pathway databases

BRENDAi3.4.22.61 3474
ReactomeiR-MMU-111465 Apoptotic cleavage of cellular proteins
R-MMU-140534 Ligand-dependent caspase activation
R-MMU-168638 NOD1/2 Signaling Pathway
R-MMU-2562578 TRIF-mediated programmed cell death
R-MMU-264870 Caspase-mediated cleavage of cytoskeletal proteins
R-MMU-3371378 Regulation by c-FLIP
R-MMU-5213460 RIPK1-mediated regulated necrosis
R-MMU-5218900 CASP8 activity is inhibited
R-MMU-5357905 Regulation of TNFR1 signaling
R-MMU-5660668 CLEC7A/inflammasome pathway
R-MMU-69416 Dimerization of procaspase-8
R-MMU-75108 Activation, myristolyation of BID and translocation to mitochondria
R-MMU-75153 Apoptotic execution phase
R-MMU-75157 FasL/ CD95L signaling
R-MMU-75158 TRAIL 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 lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 1

Organism-specific databases

MGIiMGI:1261423 Casp8

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
PropeptideiPRO_00000046321 – 218By similarityAdd BLAST218
ChainiPRO_0000004633219 – 376Caspase-8 subunit p18Add BLAST158
PropeptideiPRO_0000004634377 – 387By similarityAdd BLAST11
ChainiPRO_0000004635388 – 480Caspase-8 subunit p10Add BLAST93

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei188PhosphoserineCombined sources1
Modified residuei213PhosphoserineCombined sources1
Modified residuei226N6-acetyllysineCombined sources1
Modified residuei336PhosphotyrosineBy similarity1
Modified residuei389Phosphoserine; by CDK1By similarity1

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

EPDiO89110
PaxDbiO89110
PeptideAtlasiO89110
PRIDEiO89110

PTM databases

iPTMnetiO89110
PhosphoSitePlusiO89110

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

BgeeiENSMUSG00000026029
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

Show more details

GO - Molecular functioni

Protein-protein interaction databases

BioGridi198500, 6 interactors
DIPiDIP-37435N
IntActiO89110, 8 interactors
MINTiO89110
STRINGi10090.ENSMUSP00000027189

Structurei

3D structure databases

ProteinModelPortaliO89110
SMRiO89110
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini3 – 80DED 1PROSITE-ProRule annotationAdd BLAST78
Domaini101 – 177DED 2PROSITE-ProRule annotationAdd BLAST77

Sequence similaritiesi

Belongs to the peptidase C14A family.Curated

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG3573 Eukaryota
ENOG410ZQIE LUCA
GeneTreeiENSGT00760000118912
HOGENOMiHOG000276884
HOVERGENiHBG050803
InParanoidiO89110
KOiK04398
PhylomeDBiO89110
TreeFamiTF102023

Family and domain databases

CDDicd00032 CASc, 1 hit
InterProiView protein in InterPro
IPR033170 Caspase-8
IPR029030 Caspase-like_dom_sf
IPR033139 Caspase_cys_AS
IPR016129 Caspase_his_AS
IPR011029 DEATH-like_dom_sf
IPR001875 DED_dom
IPR002138 Pept_C14_p10
IPR001309 Pept_C14_p20
IPR015917 Pept_C14A
PANTHERiPTHR10454:SF162 PTHR10454:SF162, 1 hit
PfamiView protein in Pfam
PF01335 DED, 2 hits
PRINTSiPR00376 IL1BCENZYME
SMARTiView protein in SMART
SM00115 CASc, 1 hit
SM00031 DED, 2 hits
SUPFAMiSSF47986 SSF47986, 2 hits
SSF52129 SSF52129, 1 hit
PROSITEiView protein in 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

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)DescriptionActionsGraphical viewLength
Sequence conflicti68 – 71HISR → PHPVG in CAA04196 (Ref. 4) Curated4
Sequence conflicti94 – 99DNAQIS → RQCPRFL in CAA04196 (Ref. 4) Curated6
Sequence conflicti96A → V in CAA07677 (PubMed:9837723).Curated1
Sequence conflicti103 – 107VMLFK → SCSFR in CAA04196 (Ref. 4) Curated5
Sequence conflicti475K → N in CAA04196 (Ref. 4) Curated1

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

Similar proteinsi

Entry informationi

Entry nameiCASP8_MOUSE
AccessioniPrimary (citable) accession number: O89110
Secondary accession number(s): O35669
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 15, 2002
Last sequence update: November 1, 1998
Last modified: May 23, 2018
This is version 169 of the entry and version 1 of the sequence. See 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
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Main funding by: National Institutes of Health