ID:CASP8_HUMAN DESCRIPTION: RecName: Full=Caspase-8; Short=CASP-8; EC=3.4.22.61; AltName: Full=Apoptotic cysteine protease; AltName: Full=Apoptotic protease Mch-5; AltName: Full=CAP4; AltName: Full=FADD-homologous ICE/ced-3-like protease; AltName: Full=FADD-like ICE; Short=FLICE; AltName: Full=ICE-like apoptotic protease 5; AltName: Full=MORT1-associated ced-3 homolog; Short=MACH; Contains: RecName: Full=Caspase-8 subunit p18; Contains: RecName: Full=Caspase-8 subunit p10; Flags: Precursor; 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. Isoform 5, isoform 6, isoform 7 and isoform 8 lack the catalytic site and may interfere with the pro-apoptotic activity of the complex. 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). SUBUNIT: 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. Isoform 9 interacts at the endoplasmic reticulum with a complex containing BCAP31, BAP29, BCL2 and/or BCL2L1. Interacts with TNFAIP8L2 (By similarity). Interacts with human cytomegalovirus/HHV-5 protein vICA/UL36; this interaction inhibits CASP8 activation. INTERACTION: Self; NbExp=3; IntAct=EBI-78060, EBI-78060; P51572:BCAP31; NbExp=3; IntAct=EBI-78060, EBI-77683; Q92851:CASP10; NbExp=5; IntAct=EBI-78060, EBI-495095; Q13618:CUL3; NbExp=6; IntAct=EBI-78060, EBI-456129; Q13158:FADD; NbExp=4; IntAct=EBI-288326, EBI-494804; P25445:FAS; NbExp=12; IntAct=EBI-78060, EBI-494743; Q13418:ILK; NbExp=2; IntAct=EBI-78060, EBI-747644; Q9UDY8:MALT1; NbExp=8; IntAct=EBI-78060, EBI-1047372; O60936:NOL3; NbExp=3; IntAct=EBI-78060, EBI-740992; Q13546:RIPK1; NbExp=23; IntAct=EBI-78060, EBI-358507; O00220:TNFRSF10A; NbExp=9; IntAct=EBI-78060, EBI-518861; SUBCELLULAR LOCATION: Cytoplasm. TISSUE SPECIFICITY: Isoform 1, isoform 5 and isoform 7 are expressed in a wide variety of tissues. Highest expression in peripheral blood leukocytes, spleen, thymus and liver. Barely detectable in brain, testis and skeletal muscle. DOMAIN: Isoform 9 contains a N-terminal extension that is required for interaction with the BCAP31 complex. 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. PTM: Phosphorylated upon DNA damage, probably by ATM or ATR. 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. POLYMORPHISM: Genetic variations in CASP8 are associated with reduced risk of lung cancer [MIM:211980] in a population of Han Chinese subjects. Genetic variations are also associated with decreased risk of cancer of various other forms including esophageal, gastric, colorectal, cervical, and breast, acting in an allele dose-dependent manner. DISEASE: Defects in CASP8 are the cause of caspase-8 deficiency (CASP8D) [MIM:607271]. CASP8D is a disorder resembling autoimmune lymphoproliferative syndrome (ALPS). It is characterized by lymphadenopathy, splenomegaly, and defective CD95-induced apoptosis of peripheral blood lymphocytes (PBLs). It leads to defects in activation of T-lymphocytes, B-lymphocytes, and natural killer cells leading to immunodeficiency characterized by recurrent sinopulmonary and herpes simplex virus infections and poor responses to immunization. SIMILARITY: Belongs to the peptidase C14A family. SIMILARITY: Contains 2 DED (death effector) domains. SEQUENCE CAUTION: Sequence=CAA66858.1; Type=Miscellaneous discrepancy; Sequence=CAA66859.1; Type=Miscellaneous discrepancy; WEB RESOURCE: Name=CASP8base; Note=CASP8 mutation db; URL="http://bioinf.uta.fi/CASP8base/"; WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/CASP8"; WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/casp8/";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q14790
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
