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caspase-8; ICE-like apoptotic protease 5; MACH; MORT-1 associated CED-3 homolog; FLICE; FADD-like ICE; Mch5 (CASP8)

Multiple isoforms; 2 subunits: p18 & p10. Function: - most upstream protease of the activation cascade of caspases responsible for the TNFRSF6/FAS mediated & TNFRSF1A induced cell death - binding to the adapter molecule FADD recruits it to either receptor - the resulting aggregate, death-inducing signaling complex (DISC), performs CASP8 proteolytic activation - the active dimeric enzyme is then liberated from the DISC & free to activate downstream apoptotic proteases - proteolytic fragments of the N-terminal propeptide (CAP3, CAP5 & CAP6) are likely retained in the DISC - cleaves & activates CASP3, CASP4, CASP6, CASP7, CASP9 & CASP10 - may participate in the GZMB apoptotic pathways - cleaves ADPRT - hydrolyzes small-molecule substrate, Ac-Asp-Glu-Val-Asp-|-AMC - likely target for cowpox virus CRMA death inhibitory protein - isoforms 5, 6, 7 & 8 lack the catalytic site & may interfere with the pro-apoptotic activity of the complex - interacts with FADD, CFLAR & PEA15 - isoform 9 interacts at the endoplasmic reticulum with a complex containing BCAP31, BAP29, BCL2 &/or BCL2L1 - 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 & CASP10 can be involved in these processing events - phosphorylated upon DNA damage, probably by ATM or ATR - strict requirement for Asp at position P1 & has a preferred cleavage sequence of (Leu/Asp/Val)-Glu-Thr-Asp-|-(gly/Ser/Ala) Structure: - heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kD (p18) & a 10 kD (p10) subunit - isoform 9 contains a N-terminal extension that is required for interaction with the BCAP31 complex - belongs to the peptidase C14 family - contains 2 DED (death effector) domains Compartment: cytoplasm Alternative splicing: named isoforms=9 Expression: - isoforms 1, 5 & 7 are expressed in a wide variety of tissues - highest expression in peripheral blood leukocytes, spleen, thymus, & liver - barely detectable in brain, testis, & skeletal muscle Pathology: - defects in CASP8 are the cause of caspase-8 deficiency - gene is deleted or silenced preferentially in childhood neuroblastomas with N-myc amplification. [3] Polymorphism: - genetic vaiations in CASP8 are associated with diminished risk of lung cancer in a population of Han chinese subjects - genetic vaiations are also associated with decreased risk of cancer of various other forms including esophageal cqncer, gastric cancer, colorectal cancer, cervical cancer, & breast cancer, acting in an allele dose-dependent manner Note: - may be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay

Interactions

molecular events

General

caspase; cysteinyl aspartate-specific proteinase; ICE/CED3 family protease

Properties

SIZE: entity length = 479 aa MW = 55 kD MOTIF: DED 1 {2-80} DED 2 {100-177} Ser phosphorylation site {S188} Ser phosphorylation site {S219} domain {220-479} MOTIF: histidine residue {H317} Tyr phosphorylation site {Y334} QACQG SITE: 358-362 MOTIF: cysteine residue {C360} HOMOLOGY: caspase-1

References

  1. Boldin MP, Goncharov TM, Goltsev YV, Wallach D. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell. 1996 Jun 14;85(6):803-15. PMID: 8681376
  2. Muzio M, Chinnaiyan AM, Kischkel FC, O'Rourke K, Shevchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R, Mann M, Krammer PH, Peter ME, Dixit VM. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death--inducing signaling complex. Cell. 1996 Jun 14;85(6):817-27. PMID: 8681377
  3. Teitz T, Wei T, Valentine MB, Vanin EF, Grenet J, Valentine VA, Behm FG, Look AT, Lahti JM, Kidd VJ. Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN. Nat Med. 2000 May;6(5):529-35. PMID: 10802708
  4. CASP8base, CASP8 mutation db http://bioinf.uta.fi/CASP8base/
  5. GeneReviews https://www.genecards.org/cgi-bin/carddisp.pl?gene=CASP8
  6. UniProt :accession Q14790

Component-of

molecular complex

Databases & Figures

OMIM correlations MORBIDMAP 601763 UniProt Q14790 PFAM correlations Entrez Gene 841 KEGG correlations ENZYME 3.4.22.61 TRAIL -> caspase 8 -> bid -> smac/diablo -> IAP ...