| IED ID | IndEnz0002007721 |
| Enzyme Type ID | protease007721 |
| Protein Name |
Caspase-8 CASP-8 EC 3.4.22.61 Apoptotic cysteine protease Apoptotic protease Mch-5 CAP4 FADD-homologous ICE/ced-3-like protease FADD-like ICE FLICE ICE-like apoptotic protease 5 MORT1-associated ced-3 homolog MACH Cleaved into: Caspase-8 subunit p18; Caspase-8 subunit p10 |
| Gene Name | CASP8 MCH5 |
| Organism | Homo sapiens (Human) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Primates Haplorrhini Simiiformes Catarrhini Hominoidea (apes) Hominidae (great apes) Homininae Homo Homo sapiens (Human) |
| Enzyme Sequence | MDFSRNLYDIGEQLDSEDLASLKFLSLDYIPQRKQEPIKDALMLFQRLQEKRMLEESNLSFLKELLFRINRLDLLITYLNTRKEEMERELQTPGRAQISAYRVMLYQISEEVSRSELRSFKFLLQEEISKCKLDDDMNLLDIFIEMEKRVILGEGKLDILKRVCAQINKSLLKIINDYEEFSKERSSSLEGSPDEFSNGEELCGVMTISDSPREQDSESQTLDKVYQMKSKPRGYCLIINNHNFAKAREKVPKLHSIRDRNGTHLDAGALTTTFEELHFEIKPHDDCTVEQIYEILKIYQLMDHSNMDCFICCILSHGDKGIIYGTDGQEAPIYELTSQFTGLKCPSLAGKPKVFFIQACQGDNYQKGIPVETDSEEQPYLEMDLSSPQTRYIPDEADFLLGMATVNNCVSYRNPAEGTWYIQSLCQSLRERCPRGDDILTILTEVNYEVSNKDDKKNMGKQMPQPTFTLRKKLVFPSD |
| Enzyme Length | 479 |
| Uniprot Accession Number | Q14790 |
| Absorption | |
| Active Site | ACT_SITE 317; /evidence=ECO:0000269|PubMed:10508785; ACT_SITE 360; /evidence=ECO:0000269|PubMed:10508785 |
| Activity Regulation | ACTIVITY REGULATION: CASP8 activity is restricted by RIPK1 (By similarity). Inhibited by the effector protein NleF that is produced by pathogenic E.coli; this inhibits apoptosis (PubMed:23516580). {ECO:0000250|UniProtKB:O89110, ECO:0000269|PubMed:23516580}. |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=Strict requirement for Asp at position P1 and has a preferred cleavage sequence of (Leu/Asp/Val)-Glu-Thr-Asp-|-(Gly/Ser/Ala).; EC=3.4.22.61; Evidence={ECO:0000269|PubMed:23516580, ECO:0000269|PubMed:8962078}; |
| DNA Binding | |
| EC Number | 3.4.22.61 |
| Enzyme Function | FUNCTION: Thiol protease that plays a key role in programmed cell death by acting as a molecular switch for apoptosis, necroptosis and pyroptosis, and is required to prevent tissue damage during embryonic development and adulthood (By similarity). Initiator protease that induces extrinsic apoptosis by mediating cleavage and activation of effector caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death (PubMed:23516580, PubMed:8681376, PubMed:8681377, PubMed:9006941, PubMed:9184224, PubMed:8962078). Cleaves and activates effector caspases CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10 (PubMed:8962078, PubMed:9006941). Binding to the adapter molecule FADD recruits it to either receptor TNFRSF6/FAS mediated or TNFRSF1A (PubMed:8681376, PubMed:8681377). The resulting aggregate called death-inducing signaling complex (DISC) performs CASP8 proteolytic activation (PubMed:9184224). The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases (PubMed:9184224). Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC (PubMed:9184224). In addition to extrinsic apoptosis, also acts as a negative regulator of necroptosis: acts by cleaving RIPK1 at 'Asp-324', which is crucial to inhibit RIPK1 kinase activity, limiting TNF-induced apoptosis, necroptosis and inflammatory response (PubMed:31827280, PubMed:31827281). Also able to initiate pyroptosis by mediating cleavage and activation of gasdermin-D (GSDMD): GSDMD cleavage promoting release of the N-terminal moiety (Gasdermin-D, N-terminal) that binds to membranes and forms pores, triggering pyroptosis (By similarity). Initiates pyroptosis following inactivation of MAP3K7/TAK1 (By similarity). Also acts as a regulator of innate immunity by mediating cleavage and inactivation of N4BP1 downstream of TLR3 or TLR4, thereby promoting cytokine production (By similarity). May participate in the Granzyme B (GZMB) cell death pathways (PubMed:8755496). Cleaves PARP1 (PubMed:8681376). {ECO:0000250|UniProtKB:O89110, ECO:0000269|PubMed:23516580, ECO:0000269|PubMed:31827280, ECO:0000269|PubMed:31827281, ECO:0000269|PubMed:8681376, ECO:0000269|PubMed:8681377, ECO:0000269|PubMed:8755496, ECO:0000269|PubMed:8962078, ECO:0000269|PubMed:9006941, ECO:0000269|PubMed:9184224}.; FUNCTION: [Isoform 5]: Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex. {ECO:0000305|PubMed:8681376}.; FUNCTION: [Isoform 6]: Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex. {ECO:0000305|PubMed:8681376}.; FUNCTION: [Isoform 7]: Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex (Probable). Acts as an inhibitor of the caspase cascade (PubMed:12010809). {ECO:0000269|PubMed:12010809, ECO:0000305|PubMed:8681376}.; FUNCTION: [Isoform 8]: Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex. {ECO:0000305|PubMed:8681376}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Active site (2); Alternative sequence (10); Beta strand (20); Chain (2); Domain (2); Helix (23); Modified residue (5); Mutagenesis (3); Natural variant (3); Propeptide (2); Sequence caution (2); Sequence conflict (5); Site (3); Turn (7) |
| Keywords | 3D-structure;Acetylation;Alternative splicing;Apoptosis;Cytoplasm;Direct protein sequencing;Disease variant;Host-virus interaction;Hydrolase;Nucleus;Phosphoprotein;Protease;Reference proteome;Repeat;Thiol protease;Zymogen |
| Interact With | P05067; P10275; P51572; Q92851; Itself; Q9UKL3; O15519; O15519-1; Q13618; Q13158; P25445; P25445-1; P48023; Q06787-7; Q13418; Q9UDY8; O60936; P53350; P29350; P04049; Q13546; Q969K3; P21580; O00220; P13051-2; Q96AX1; Q13158; O15519-1; Q13158; Q14790 |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9JHX4}. Nucleus {ECO:0000250|UniProtKB:Q9JHX4}. |
| Modified Residue | MOD_RES 188; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:O89110; MOD_RES 211; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:O89110; MOD_RES 224; /note=N6-acetyllysine; /evidence=ECO:0000250|UniProtKB:O89110; MOD_RES 334; /note=Phosphotyrosine; /evidence=ECO:0007744|PubMed:15592455; MOD_RES 387; /note=Phosphoserine; by CDK1; /evidence=ECO:0000269|PubMed:20937773 |
| Post Translational Modification | PTM: (Microbial infection) Proteolytically cleaved by the cowpox virus CRMA death inhibitory protein. {ECO:0000269|PubMed:8962078}.; PTM: 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. {ECO:0000269|PubMed:8962078, ECO:0000269|PubMed:9184224}.; PTM: Phosphorylation on Ser-387 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. {ECO:0000269|PubMed:20937773}. |
| Signal Peptide | |
| Structure 3D | NMR spectroscopy (1); Electron microscopy (1); X-ray crystallography (19) |
| Cross Reference PDB | 1F9E; 1I4E; 1QDU; 1QTN; 2C2Z; 2FUN; 2K7Z; 2Y1L; 3H11; 3KJN; 3KJQ; 4JJ7; 4PRZ; 4PS1; 4ZBW; 5H31; 5H33; 5JQE; 5L08; 6AGW; 6PX9; |
| Mapped Pubmed ID | 10235259; 10329646; 10521396; 10837247; 10891503; 10894160; 10964557; 11002417; 11098060; 11260720; 11384965; 11420686; 11423904; 11437602; 11463813; 11717445; 11751897; 12065591; 12107169; 12181749; 12198154; 12215447; 12598529; 12620239; 12620240; 12646168; 12668660; 12692130; 12709429; 12752666; 12804595; 12884866; 12887920; 12912912; 14612908; 14739303; 14970175; 15024054; 15254227; 15289496; 15637055; 1574116; 15760909; 15814722; 16135563; 16169070; 16183855; 16492559; 16498403; 16585540; 16618810; 16619028; 16936772; 16970398; 17047155; 17159907; 17170703; 17290218; 17442709; 17644308; 18086677; 18089778; 18154733; 18190721; 18216014; 18245485; 18256533; 18328427; 18398042; 18455983; 18458084; 18485876; 18761323; 18838202; 18974049; 19124506; 19176810; 19278658; 19416807; 19427028; 19524512; 19524513; 19632185; 19665028; 19683492; 19773279; 19851329; 20097879; 20103630; 20124702; 20218968; 20219915; 20308068; 20580860; 20696707; 20711500; 20951169; 21157428; 21183680; 21183955; 21235526; 21458669; 21459798; 21525013; 21525171; 21625644; 21737329; 21737330; 21785459; 21803845; 21822306; 21900206; 21988832; 22173242; 22266862; 22267217; 22274400; 22421964; 22505256; 22810585; 22817896; 23305266; 23614665; 23678861; 24100030; 24342355; 24438025; 25043603; 25079698; 25640309; 25790448; 25911380; 26003730; 26036637; 27109099; 27195913; 27325299; 27432652; 27462786; 27746017; 27821809; 28405521; 29681455; 30206319; 30501030; 31511692; 31927936; 7531702; 7667287; 9027312; 9049422; 9065443; 9343261; 9624166; 9721089; 9880531; |
| Motif | |
| Gene Encoded By | |
| Mass | 55,391 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | |
| Cross Reference Brenda | 3.4.22.61; |