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Protein

Caspase-8

Gene

Casp8

Organism
Rattus norvegicus (Rat)
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.By similarity

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).By similarity

Enzyme regulationi

Inhibited by CRMA and P35.By similarity

Sites

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

GO - Molecular functioni

  • cysteine-type endopeptidase activity Source: RGD
  • cysteine-type endopeptidase activity involved in apoptotic process Source: UniProtKB
  • cysteine-type endopeptidase activity involved in apoptotic signaling pathway Source: Ensembl
  • death receptor binding Source: RGD
  • protein complex binding Source: RGD
  • tumor necrosis factor receptor binding Source: RGD

GO - Biological processi

  • activation of cysteine-type endopeptidase activity Source: Ensembl
  • apoptotic process Source: RGD
  • cellular response to mechanical stimulus Source: Ensembl
  • cellular response to organic cyclic compound Source: RGD
  • execution phase of apoptosis Source: UniProtKB
  • negative regulation of I-kappaB kinase/NF-kappaB signaling Source: Ensembl
  • positive regulation of I-kappaB kinase/NF-kappaB signaling Source: Ensembl
  • positive regulation of macrophage differentiation Source: Ensembl
  • protein heterooligomerization Source: RGD
  • proteolysis Source: RGD
  • proteolysis involved in cellular protein catabolic process Source: Ensembl
  • regulation of apoptotic process Source: InterPro
  • response to antibiotic Source: RGD
  • response to cobalt ion Source: RGD
  • response to cold Source: RGD
  • response to estradiol Source: RGD
  • response to ethanol Source: RGD
  • response to lipopolysaccharide Source: RGD
  • response to tumor necrosis factor Source: Ensembl
  • TRAIL-activated apoptotic signaling pathway Source: Ensembl
Complete GO annotation...

Keywords - Molecular functioni

Hydrolase, Protease, Thiol protease

Keywords - Biological processi

Apoptosis

Enzyme and pathway databases

BRENDAi3.4.22.61. 5301.
ReactomeiR-RNO-111465. Apoptotic cleavage of cellular proteins.
R-RNO-168638. NOD1/2 Signaling Pathway.
R-RNO-264870. Caspase-mediated cleavage of cytoskeletal proteins.
R-RNO-3371378. Regulation by c-FLIP.
R-RNO-5213460. RIPK1-mediated regulated necrosis.
R-RNO-5218900. CASP8 activity is inhibited.
R-RNO-5357905. Regulation of TNFR1 signaling.
R-RNO-5660668. CLEC7A/inflammasome pathway.
R-RNO-69416. Dimerization of procaspase-8.
R-RNO-75108. Activation, myristolyation of BID and translocation to mitochondria.
R-RNO-75153. Apoptotic execution phase.
R-RNO-75157. FasL/ CD95L signaling.
R-RNO-75158. TRAIL signaling.

Protein family/group databases

MEROPSiC14.009.

Names & Taxonomyi

Protein namesi
Recommended name:
Caspase-81 PublicationCurated (EC:3.4.22.61)
Short name:
CASP-8
Cleaved into the following 2 chains:
Gene namesi
Name:Casp8Imported
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Chromosome 9

Organism-specific databases

RGDi620945. Casp8.

Subcellular locationi

GO - Cellular componenti

  • CD95 death-inducing signaling complex Source: RGD
  • cell body Source: RGD
  • cytosol Source: RGD
  • death-inducing signaling complex Source: RGD
  • membrane raft Source: RGD
  • microtubule organizing center Source: Ensembl
  • mitochondrion Source: Ensembl
  • neuron projection Source: RGD
  • nucleoplasm Source: Ensembl
  • protein complex Source: RGD
  • ripoptosome Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Propeptidei1 – 218218By similarityPRO_0000432425Add
BLAST
Chaini219 – 378160Caspase-8 subunit p18PRO_0000432426Add
BLAST
Propeptidei379 – 38810By similarityPRO_0000432427
Chaini389 – 48294Caspase-8 subunit p10PRO_0000432428Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei188 – 1881PhosphoserineBy similarity
Modified residuei213 – 2131PhosphoserineBy similarity
Modified residuei336 – 3361PhosphotyrosineBy similarity
Modified residuei390 – 3901Phosphoserine; 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

Phosphoprotein, Zymogen

Proteomic databases

PaxDbiQ9JHX4.
PRIDEiQ9JHX4.

PTM databases

iPTMnetiQ9JHX4.

Expressioni

Gene expression databases

GenevisibleiQ9JHX4. RN.

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 similarity1 Publication

Binary interactionsi

WithEntry#Exp.IntActNotes
FaddQ8R2E72EBI-4326675,EBI-4326723

GO - Molecular functioni

  • death receptor binding Source: RGD
  • protein complex binding Source: RGD
  • tumor necrosis factor receptor binding Source: RGD

Protein-protein interaction databases

IntActiQ9JHX4. 2 interactions.
STRINGi10116.ENSRNOP00000016613.

Structurei

3D structure databases

ProteinModelPortaliQ9JHX4.
SMRiQ9JHX4. Positions 225-480.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini2 – 8079DED 1PROSITE-ProRule annotationAdd
BLAST
Domaini100 – 17778DED 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

eggNOGiKOG3573. Eukaryota.
ENOG410ZQIE. LUCA.
GeneTreeiENSGT00760000118912.
HOGENOMiHOG000276884.
HOVERGENiHBG050803.
KOiK04398.
OMAiQRKQEPI.
OrthoDBiEOG7CRTQM.
PhylomeDBiQ9JHX4.
TreeFamiTF102023.

Family and domain databases

Gene3Di1.10.533.10. 2 hits.
3.40.50.1460. 1 hit.
InterProiIPR033170. Caspase-8.
IPR029030. Caspase-like_dom.
IPR033139. Caspase_cys_AS.
IPR016129. Caspase_his_AS.
IPR011029. DEATH-like_dom.
IPR001875. DED_dom.
IPR002138. Pept_C14_p10.
IPR001309. Pept_C14_p20.
IPR015917. Pept_C14A.
[Graphical view]
PANTHERiPTHR10454:SF162. PTHR10454:SF162. 1 hit.
PfamiPF01335. DED. 2 hits.
[Graphical view]
PRINTSiPR00376. IL1BCENZYME.
SMARTiSM00115. CASc. 1 hit.
SM00031. DED. 2 hits.
[Graphical view]
SUPFAMiSSF47986. SSF47986. 2 hits.
SSF52129. SSF52129. 1 hit.
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.

Q9JHX4-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MDFHSCLYDI AERLGNEELA ALKFLCLDHI PQKKQESIND VLVLFQRLQE
60 70 80 90 100
EGMLEEDNLS FLKELLFHIS RRDLLSRVLK SSPEEMVREL QVLGKAQVSA
110 120 130 140 150
YRVMLFKLSE DMDKEDLKSF KFLLITEIPK CKLQDNSSLL DIFVEMEKRT
160 170 180 190 200
ILAENNLVTL KSICFRVNRS LLGRIDDYER SSTERRMSTE GGEELPVSVL
210 220 230 240 250
DEVTIKMQDM WDSPGEQESE SLNSDNVYQM KSKPRGYCLI FNNNNFSKAR
260 270 280 290 300
EDIPKLSNMR DRKGTNYDEE ALSKTFKELH FEIVSFSDCT ASQIHEVLVS
310 320 330 340 350
YQSKDHKGKD CFICCILSHG DKGIVYGTDG KEASIYELTS YFTGSKCPSL
360 370 380 390 400
AGKPKIFFIQ ACQGNNFQKA VPVPDETGLE QEHVLEEDSS SYKNYIPDEA
410 420 430 440 450
DFLLGMATVK NCVSYRDPTR GTWYIQSLCQ SLRERCPRGE DILSILTGVN
460 470 480
YDVSNKDNPR NMGKQMPQPI FTLRKKLFFP PN
Length:482
Mass (Da):55,339
Last modified:October 1, 2000 - v1
Checksum:i82B4A29330C53264
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF279308 mRNA. Translation: AAF87778.1.
AF288372 mRNA. Translation: AAK83055.1.
AABR06060567 Genomic DNA. No translation available.
AABR06060568 Genomic DNA. No translation available.
CH473965 Genomic DNA. Translation: EDL98978.1.
CH473965 Genomic DNA. Translation: EDL98979.1.
RefSeqiNP_071613.1. NM_022277.1.
XP_006245077.1. XM_006245015.2.
UniGeneiRn.54474.

Genome annotation databases

EnsembliENSRNOT00000016613; ENSRNOP00000016613; ENSRNOG00000012331.
ENSRNOT00000084498; ENSRNOP00000069982; ENSRNOG00000012331.
GeneIDi64044.
KEGGirno:64044.
UCSCiRGD:620945. rat.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF279308 mRNA. Translation: AAF87778.1.
AF288372 mRNA. Translation: AAK83055.1.
AABR06060567 Genomic DNA. No translation available.
AABR06060568 Genomic DNA. No translation available.
CH473965 Genomic DNA. Translation: EDL98978.1.
CH473965 Genomic DNA. Translation: EDL98979.1.
RefSeqiNP_071613.1. NM_022277.1.
XP_006245077.1. XM_006245015.2.
UniGeneiRn.54474.

3D structure databases

ProteinModelPortaliQ9JHX4.
SMRiQ9JHX4. Positions 225-480.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiQ9JHX4. 2 interactions.
STRINGi10116.ENSRNOP00000016613.

Protein family/group databases

MEROPSiC14.009.

PTM databases

iPTMnetiQ9JHX4.

Proteomic databases

PaxDbiQ9JHX4.
PRIDEiQ9JHX4.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSRNOT00000016613; ENSRNOP00000016613; ENSRNOG00000012331.
ENSRNOT00000084498; ENSRNOP00000069982; ENSRNOG00000012331.
GeneIDi64044.
KEGGirno:64044.
UCSCiRGD:620945. rat.

Organism-specific databases

CTDi841.
RGDi620945. Casp8.

Phylogenomic databases

eggNOGiKOG3573. Eukaryota.
ENOG410ZQIE. LUCA.
GeneTreeiENSGT00760000118912.
HOGENOMiHOG000276884.
HOVERGENiHBG050803.
KOiK04398.
OMAiQRKQEPI.
OrthoDBiEOG7CRTQM.
PhylomeDBiQ9JHX4.
TreeFamiTF102023.

Enzyme and pathway databases

BRENDAi3.4.22.61. 5301.
ReactomeiR-RNO-111465. Apoptotic cleavage of cellular proteins.
R-RNO-168638. NOD1/2 Signaling Pathway.
R-RNO-264870. Caspase-mediated cleavage of cytoskeletal proteins.
R-RNO-3371378. Regulation by c-FLIP.
R-RNO-5213460. RIPK1-mediated regulated necrosis.
R-RNO-5218900. CASP8 activity is inhibited.
R-RNO-5357905. Regulation of TNFR1 signaling.
R-RNO-5660668. CLEC7A/inflammasome pathway.
R-RNO-69416. Dimerization of procaspase-8.
R-RNO-75108. Activation, myristolyation of BID and translocation to mitochondria.
R-RNO-75153. Apoptotic execution phase.
R-RNO-75157. FasL/ CD95L signaling.
R-RNO-75158. TRAIL signaling.

Miscellaneous databases

PROiQ9JHX4.

Gene expression databases

GenevisibleiQ9JHX4. RN.

Family and domain databases

Gene3Di1.10.533.10. 2 hits.
3.40.50.1460. 1 hit.
InterProiIPR033170. Caspase-8.
IPR029030. Caspase-like_dom.
IPR033139. Caspase_cys_AS.
IPR016129. Caspase_his_AS.
IPR011029. DEATH-like_dom.
IPR001875. DED_dom.
IPR002138. Pept_C14_p10.
IPR001309. Pept_C14_p20.
IPR015917. Pept_C14A.
[Graphical view]
PANTHERiPTHR10454:SF162. PTHR10454:SF162. 1 hit.
PfamiPF01335. DED. 2 hits.
[Graphical view]
PRINTSiPR00376. IL1BCENZYME.
SMARTiSM00115. CASc. 1 hit.
SM00031. DED. 2 hits.
[Graphical view]
SUPFAMiSSF47986. SSF47986. 2 hits.
SSF52129. SSF52129. 1 hit.
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. Itoh T., Itoh A., Pleasure D.
    Submitted (JUN-2000) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    Strain: Sprague-Dawley.
  2. "Molecular cloning and characterization of rat caspase-8: Its implication in delayed neuronal cell death after ischemia."
    Cao G., Graham S.H., Chen D., Chen J.
    Submitted (JUL-2000) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    Strain: Sprague-Dawley.
    Tissue: Cerebellum.
  3. "Genome sequence of the Brown Norway rat yields insights into mammalian evolution."
    Gibbs R.A., Weinstock G.M., Metzker M.L., Muzny D.M., Sodergren E.J., Scherer S., Scott G., Steffen D., Worley K.C., Burch P.E., Okwuonu G., Hines S., Lewis L., Deramo C., Delgado O., Dugan-Rocha S., Miner G., Morgan M.
    , Hawes A., Gill R., Holt R.A., Adams M.D., Amanatides P.G., Baden-Tillson H., Barnstead M., Chin S., Evans C.A., Ferriera S., Fosler C., Glodek A., Gu Z., Jennings D., Kraft C.L., Nguyen T., Pfannkoch C.M., Sitter C., Sutton G.G., Venter J.C., Woodage T., Smith D., Lee H.-M., Gustafson E., Cahill P., Kana A., Doucette-Stamm L., Weinstock K., Fechtel K., Weiss R.B., Dunn D.M., Green E.D., Blakesley R.W., Bouffard G.G., De Jong P.J., Osoegawa K., Zhu B., Marra M., Schein J., Bosdet I., Fjell C., Jones S., Krzywinski M., Mathewson C., Siddiqui A., Wye N., McPherson J., Zhao S., Fraser C.M., Shetty J., Shatsman S., Geer K., Chen Y., Abramzon S., Nierman W.C., Havlak P.H., Chen R., Durbin K.J., Egan A., Ren Y., Song X.-Z., Li B., Liu Y., Qin X., Cawley S., Cooney A.J., D'Souza L.M., Martin K., Wu J.Q., Gonzalez-Garay M.L., Jackson A.R., Kalafus K.J., McLeod M.P., Milosavljevic A., Virk D., Volkov A., Wheeler D.A., Zhang Z., Bailey J.A., Eichler E.E., Tuzun E., Birney E., Mongin E., Ureta-Vidal A., Woodwark C., Zdobnov E., Bork P., Suyama M., Torrents D., Alexandersson M., Trask B.J., Young J.M., Huang H., Wang H., Xing H., Daniels S., Gietzen D., Schmidt J., Stevens K., Vitt U., Wingrove J., Camara F., Mar Alba M., Abril J.F., Guigo R., Smit A., Dubchak I., Rubin E.M., Couronne O., Poliakov A., Huebner N., Ganten D., Goesele C., Hummel O., Kreitler T., Lee Y.-A., Monti J., Schulz H., Zimdahl H., Himmelbauer H., Lehrach H., Jacob H.J., Bromberg S., Gullings-Handley J., Jensen-Seaman M.I., Kwitek A.E., Lazar J., Pasko D., Tonellato P.J., Twigger S., Ponting C.P., Duarte J.M., Rice S., Goodstadt L., Beatson S.A., Emes R.D., Winter E.E., Webber C., Brandt P., Nyakatura G., Adetobi M., Chiaromonte F., Elnitski L., Eswara P., Hardison R.C., Hou M., Kolbe D., Makova K., Miller W., Nekrutenko A., Riemer C., Schwartz S., Taylor J., Yang S., Zhang Y., Lindpaintner K., Andrews T.D., Caccamo M., Clamp M., Clarke L., Curwen V., Durbin R.M., Eyras E., Searle S.M., Cooper G.M., Batzoglou S., Brudno M., Sidow A., Stone E.A., Payseur B.A., Bourque G., Lopez-Otin C., Puente X.S., Chakrabarti K., Chatterji S., Dewey C., Pachter L., Bray N., Yap V.B., Caspi A., Tesler G., Pevzner P.A., Haussler D., Roskin K.M., Baertsch R., Clawson H., Furey T.S., Hinrichs A.S., Karolchik D., Kent W.J., Rosenbloom K.R., Trumbower H., Weirauch M., Cooper D.N., Stenson P.D., Ma B., Brent M., Arumugam M., Shteynberg D., Copley R.R., Taylor M.S., Riethman H., Mudunuri U., Peterson J., Guyer M., Felsenfeld A., Old S., Mockrin S., Collins F.S.
    Nature 428:493-521(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    Strain: Brown Norway.
  4. Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.
    Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    Strain: Brown Norway.
  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. "Quantitative maps of protein phosphorylation sites across 14 different rat organs and tissues."
    Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C., Olsen J.V.
    Nat. Commun. 3:876-876(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].

Entry informationi

Entry nameiCASP8_RAT
AccessioniPrimary (citable) accession number: Q9JHX4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 1, 2015
Last sequence update: October 1, 2000
Last modified: June 8, 2016
This is version 122 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. Peptidase families
    Classification of peptidase families and list of entries
  2. SIMILARITY comments
    Index of protein domains and families

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 one 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.