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O89110

- CASP8_MOUSE

UniProt

O89110 - CASP8_MOUSE

Protein

Caspase-8

Gene

Casp8

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 137 (01 Oct 2014)
      Sequence version 1 (01 Nov 1998)
      Previous versions | rss
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    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

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

    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. death effector domain binding Source: RefGenome
    4. endopeptidase activity Source: MGI
    5. peptidase activity Source: MGI
    6. protein binding Source: IntAct
    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

    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.

    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. centrosome Source: Ensembl
    4. cytoplasm Source: MGI
    5. membrane raft 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

    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

    ArrayExpressiO89110.
    BgeeiO89110.
    CleanExiMM_CASP8.
    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 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

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    MDFQSCLYAI AEELGSEDLA ALKFLCLDYI PHKKQETIED AQKLFLRLRE    50
    KGMLEEGNLS FLKELLFHIS RWDLLVNFLD CNREEMVREL RDPDNAQISP 100
    YRVMLFKLSE EVSELELRSF KFLLNNEIPK CKLEDDLSLL EIFVEMEKRT 150
    MLAENNLETL KSICDQVNKS LLGKIEDYER SSTERRMSLE GREELPPSVL 200
    DEMSLKMAEL CDSPREQDSE SRTSDKVYQM KNKPRGYCLI INNHDFSKAR 250
    EDITQLRKMK DRKGTDCDKE ALSKTFKELH FEIVSYDDCT ANEIHEILEG 300
    YQSADHKNKD CFICCILSHG DKGVVYGTDG KEASIYDLTS YFTGSKCPSL 350
    SGKPKIFFIQ ACQGSNFQKG VPDEAGFEQQ NHTLEVDSSS HKNYIPDEAD 400
    FLLGMATVKN CVSYRDPVNG TWYIQSLCQS LRERCPQGDD ILSILTGVNY 450
    DVSNKDDRRN KGKQMPQPTF TLRKKLFFPP 480
    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:
    EMBL
    GenBank
    DDBJ
    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:
    EMBL
    GenBank
    DDBJ
    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.

    Miscellaneous databases

    NextBioi 281064.
    PROi O89110.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi O89110.
    Bgeei O89110.
    CleanExi MM_CASP8.
    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

    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.
    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: October 1, 2014
    This is version 137 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