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Literature summary for 3.4.22.61 extracted from
- Proliferative versus apoptotic functions of caspase-8 hetero or homo: the caspase-8 dimer controls cell fate (2012), Biochim. Biophys. Acta, 1824, 113-122.
Activating Compound
| Activating Compound | Comment | Organism | Structure |
|---|---|---|---|
| FLIPL protein | a catalytically defective caspase-8 paralogue, can interact with caspase-8 to activate its catalytic function | Mus musculus | |
| FLIPL protein | a catalytically defective caspase-8 paralogue, can interact with caspase-8 to activate its catalytic function | Homo sapiens |
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| Ac-IETD-CHO | - |
Homo sapiens |  |
| Ac-IETD-CHO | - |
Mus musculus | |
| FLIPL protein | inhibits cleavage of Bid | Homo sapiens | |
| Z-EVD-chloromethylketone | - |
Homo sapiens | |
| Z-EVD-chloromethylketone | - |
Mus musculus | |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| FLIPL protein + H2O | Mus musculus | processing of free FLIPL by caspase-8, FLIPL cleavage increases the recruitment of caspase-8 | ? | - |
? | |
| FLIPL protein + H2O | Homo sapiens | processing of free FLIPL by caspase-8, FLIPL cleavage increases the recruitment of caspase-8 | ? | - |
? | |
| additional information | Mus musculus | caspase-8 performs self-cleavage to give the processed active dimer. Within the caspase-8/FLIPL heterodimer, caspase-8 prefers to process FLIPL over itself | ? | - |
? | |
| additional information | Homo sapiens | caspase-8 performs self-cleavage to give the processed active dimer. Within the caspase-8/FLIPL heterodimer, caspase-8 prefers to process FLIPL over itself | ? | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | - |
- |
- |
| Mus musculus | - |
- |
- |
Posttranslational Modification
| Posttranslational Modification | Comment | Organism |
|---|---|---|
| proteolytic modification | caspase-8 is activated at the DISC, downstream of death-receptor signaling. Caspases-8 and -10 are recruited to the DISC as intact monomers and recruitment of the caspases to the DISC subsequently leads to their dimerization and activation through induced proximity, mechanism, overview. Human caspase-8 is cleaved twice in the intersubunit linker | Homo sapiens |
| proteolytic modification | caspase-8 is activated at the DISC, downstream of death-receptor signaling. Mouse caspase-8 only has one cleavage site in the ubunit linker | Mus musculus |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| endothelial cell | of the heart and vascular system | Mus musculus | - |
| heart | - |
Mus musculus | - |
| lymphocyte | - |
Mus musculus | - |
| monocyte | - |
Mus musculus | - |
| vascular system | - |
Mus musculus | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| BID + H2O | - |
Homo sapiens | ? | - |
? | |
| FLIPL protein + H2O | processing of free FLIPL by caspase-8, FLIPL cleavage increases the recruitment of caspase-8 | Mus musculus | ? | - |
? | |
| FLIPL protein + H2O | processing of free FLIPL by caspase-8, FLIPL cleavage increases the recruitment of caspase-8 | Homo sapiens | ? | - |
? | |
| FLIPL protein + H2O | processing of free FLIPL by caspase-8 | Mus musculus | ? | - |
? | |
| FLIPL protein + H2O | processing of free FLIPL by caspase-8 | Homo sapiens | ? | - |
? | |
| additional information | caspase-8 performs self-cleavage to give the processed active dimer. Within the caspase-8/FLIPL heterodimer, caspase-8 prefers to process FLIPL over itself | Mus musculus | ? | - |
? | |
| additional information | caspase-8 performs self-cleavage to give the processed active dimer. Within the caspase-8/FLIPL heterodimer, caspase-8 prefers to process FLIPL over itself | Homo sapiens | ? | - |
? | |
| additional information | the substrate cleft is closed in the monomeric zymogen, whereas the cleft is accessible for substrate binding in both dimers, binding structure, overview | Mus musculus | ? | - |
? | |
| additional information | the substrate cleft is closed in the monomeric zymogen, whereas the cleft is accessible for substrate binding in both dimers, binding structure, overview | Homo sapiens | ? | - |
? | |
Subunits
| Subunits | Comment | Organism |
|---|---|---|
| dimer | processed active enzyme, during dimerization, a loop containing a small helix translocates from the active site | Mus musculus |
| dimer | processed active enzyme, during dimerization, a loop containing a small helix translocates from the active site, mechanism, overview | Homo sapiens |
| monomer | inactive zymogen, the monomeric form of caspase-8 has a typical caspase fold, consisting of a six-stranded beta sheet formed by five parallel and one anti-parallel beta strand, overview | Mus musculus |
| monomer | inactive zymogen, the monomeric form of caspase-8 has a typical caspase fold, consisting of a six-stranded beta sheet formed by five parallel and one anti-parallel beta strand, overview | Homo sapiens |
| More | caspases can only be active as dimers, since neither the active site dyad nor the substrate pocket can be formed in the monomeric form, structure analysis and comparison of caspase-8 monomeric zymogen and the substrate-bound, fully-processed, caspase-8 dimer, overview | Mus musculus |
| More | caspases can only be active as dimers, since neither the active site dyad nor the substrate pocket can be formed in the monomeric form, structure analysis and comparison of caspase-8 monomeric zymogen and the substrate-bound, fully-processed, caspase-8 dimer, overview | Homo sapiens |
General Information
| General Information | Comment | Organism |
|---|---|---|
| evolution | initiator and executioner caspases, the pro-apoptotic members of the caspase family are subdivided in the initiators of apoptosis and the executioners of apoptosis. Caspase-18 and the ancestor of -8 and -10 called caspase-810 in this schematic are still found in fishes. Later on in evolution, caspase-8 and -10 branched off from caspase-810 | Mus musculus |
| evolution | initiator and executioner caspases, the pro-apoptotic members of the caspase family are subdivided in the initiators of apoptosis, i.e. caspases-8, -9 and -10 in humans, and the executioners of apoptosis, caspase-3, -6 and -7, phylogenetic tree of all the human caspases, overview. The initiators have a relatively large N-terminal dimerization domain, either a death effector domain, caspases-8 and -10, or a structurally related caspase recruitment domain, caspase-9. Caspase-18 and the ancestor of -8 and -10 called caspase-810 in this schematic are still found in fishes. Later on in evolution, caspase-8 and -10 branched off from caspase-810 | Homo sapiens |
| malfunction | mice deficient in caspase-8 in basal epidermal keratinocytes suffer from chronic skin inflammation, as an apparent consequence of IRF3 hyper-activation. Catalytically active caspase-8 is required to rescue the lymphocyte development in caspase-8 deficient mice. The developmental phenotype observed in the caspase-8 knockout mouse is shared with both the FLIPL knockout and the FADD knockout | Mus musculus |
| additional information | FLIPL, a catalytically defective caspase-8 paralog, can interact with caspase-8 to activate its catalytic function. The caspase-8/FLIPL heterodimer has a restricted substrate repertoire and does not induce apoptosis. Caspase-8 heterodimerized with FLIPL prevents the receptor interacting kinases RIPK1 and -3 from executing the form of cell death known as necroptosis | Mus musculus |
| additional information | FLIPL, a catalytically defective caspase-8 paralog, can interact with caspase-8 to activate its catalytic function. The caspase-8/FLIPL heterodimer has a restricted substrate repertoire and does not induce apoptosis. Caspase-8 heterodimerized with FLIPL prevents the receptor interacting kinases RIPK1 and -3 from executing the form of cell death known as necroptosis | Homo sapiens |
| physiological function | caspase-8, the initiator of extrinsically-triggered apoptosis, also has important functions in cellular activation and differentiation downstream of a variety of cell surface receptors. The heterodimer of caspase-8 with the long isoform of cellular FLIP, FLIPL, fulfills these pro-survival functions of caspase-8. Caspase-8 has important functions in survival and development, caspase-8 activation not only triggers apoptosis but is also essential for embryonic development. Tissue specific knockout of caspase-8 revealed an essential role for this caspase in the development of a variety of tissues,most notably the endothelial cells of the heart and vascular system, lymphocytes and monocytes. Caspase-8 in programmed necrosis, detailed overview | Mus musculus |
| physiological function | caspase-8, the initiator of extrinsically-triggered apoptosis, also has important functions in cellular activation and differentiation downstream of a variety of cell surface receptors. The heterodimer of caspase-8 with the long isoform of cellular FLIP, FLIPL, fulfills these pro-survival functions of caspase-8. Caspase-8 has important functions in survival and development. Caspase-8 in programmed necrosis, detailed overview | Homo sapiens |
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