CD95 death-inducing signaling complex
Definition
Target type: cellularcomponent
A protein complex formed upon binding of Fas/CD95/APO-1 to its ligand. The complex includes FADD/Mort1, procaspase-8/10 and c-FLIP in addition to the ligand-bound receptor. [PMID:12628743, PMID:12655293]
The CD95 death-inducing signaling complex (DISC) is a multiprotein complex that forms on the cytoplasmic face of the plasma membrane upon stimulation of the CD95 (also known as Fas or APO-1) receptor by its ligand, CD95L. The DISC is a key component of the extrinsic pathway of apoptosis, a programmed cell death process that is essential for the maintenance of tissue homeostasis and the elimination of damaged or unwanted cells. The DISC is composed of several key proteins:
1. **CD95 Receptor:** The CD95 receptor is a type I transmembrane protein that belongs to the tumor necrosis factor (TNF) receptor superfamily. It is expressed on the surface of most mammalian cells and is responsible for initiating the extrinsic pathway of apoptosis.
2. **FADD:** FADD (Fas-associated death domain protein) is an adaptor protein that contains a death domain (DD) and a death effector domain (DED). FADD interacts with the DD of CD95 via its DD and recruits the procaspase-8 via its DED.
3. **Procaspase-8:** Procaspase-8 is a cysteine protease that is inactive in its proform. Upon recruitment to the DISC, procaspase-8 is activated by autocatalytic cleavage, resulting in the formation of the active caspase-8.
4. **cFLIP:** cFLIP (cellular FLICE-inhibitory protein) is a protein that shares significant homology with procaspase-8. It can bind to FADD but lacks the catalytic activity of caspase-8, acting as a negative regulator of caspase-8 activation.
The assembly of the DISC is initiated by the binding of CD95L to CD95, triggering the recruitment of FADD and procaspase-8. This process is facilitated by the DD-DD interaction between CD95 and FADD and the DED-DED interaction between FADD and procaspase-8. Once assembled, the DISC serves as a platform for the activation of caspase-8, which then initiates the downstream caspase cascade leading to apoptotic cell death.
The DISC is a dynamic structure whose composition and function can be regulated by a number of factors, including the expression levels of its components, the availability of CD95L, and the presence of inhibitors such as cFLIP. The regulation of DISC formation and function is crucial for maintaining cellular homeostasis and preventing inappropriate apoptosis.'
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Proteins (2)
| Protein | Definition | Taxonomy |
|---|---|---|
| Caspase-10 | A caspase-10 that is encoded in the genome of human. [PRO:WCB, UniProtKB:Q92851] | Homo sapiens (human) |
| Caspase-8 | A caspase-8 that is encoded in the genome of human. [PRO:DNx] | Homo sapiens (human) |
Compounds (16)
| Compound | Definition | Classes | Roles |
|---|---|---|---|
| 3,3',4,5'-tetrahydroxystilbene | stilbenoid | ||
| isoquinoline-1,3,4-trione | isoquinoline-1,3,4-trione: structure in first source | ||
| n-methylisatin | N-methylisatin: structure given in first source | ||
| 2,2'-((3,3'-dimethoxy(1,1'-biphenyl)-4,4'-diyl)diimino)bis-benzoic acid | 2,2'-((3,3'-dimethoxy(1,1'-biphenyl)-4,4'-diyl)diimino)bis-benzoic acid: structure given in first source | ||
| stictic acid | stictic acid: antioxidant from lichen, Usnea articulata; structure in first source | aromatic ether | |
| pralnacasan | pralnacasan: NSAID, ICE inhibitor & metastasis inhibitor; RN & structure in first source | ||
| 1,3(2h,4h)-isoquinolinedione | 1,3(2H,4H)-isoquinolinedione: structure in first source | ||
| acetyl-aspartyl-glutamyl-valyl-aspartal | Ac-Asp-Glu-Val-Asp-H : A tetrapeptide consisting of two L-aspartic acid residues, an L-glutamyl residue and an L-valine residue with an acetyl group at the N-terminal and with the C-terminal carboxy group reduced to an aldehyde. It is an inhibitor of caspase-3/7. acetyl-aspartyl-glutamyl-valyl-aspartal: a capase inhibitor | tetrapeptide | protease inhibitor |
| 1,6-dimethyl-3-(2-pyridinyl)pyrimido[5,4-e][1,2,4]triazine-5,7-dione | pyrimidotriazine | ||
| 1,6-dimethyl-3-propylpyrimido[5,4-e][1,2,4]triazine-5,7-dione | pyrimidotriazine | ||
| 5-Nitroisatin | indoles | anticoronaviral agent | |
| n-acetyltyrosyl-valyl-alanyl-aspartyl aldehyde | |||
| benzyloxycarbonyl-phe-ala-fluormethylketone | cathepsin B inhibitor : A cysteine protease inhibitor which inhibits cathepsin B (EC 3.4.22.1). | ||
| benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone | |||
| grassystatin a | grassystatin A: isolated from a cyanobacterium, identified as Lyngbya cf.; structure in first source | ||
| MK-8353 | MK-8353 : A member of the class of indazoles that is 1H-indazole substituted by a 6-(propan-2-yloxy)pyridin-3-yl group at position 3 and by a {[(3S)-3-(methylsulfanyl)-1-(2-{4-[4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]-3,6-dihydropyridin-1(2H)-yl}-2-oxoethyl)pyrrolidin-3-yl]carbonyl}amino group at position 5. It is a potent and selective inhibitor of ERK1 and ERK2 in vitro (IC50 values of 23.0 nM and 8.8 nM, respectively). The drug is being developed by Merck Sharp & Dohme and is currently in clinical development for the treatment of advanced/metastatic solid tumors. MK-8353: ERK inhibitor used in oncology | aromatic ether; dihydropyridine; indazoles; methyl sulfide; N-alkylpyrrolidine; pyridines; pyrrolidinecarboxamide; secondary carboxamide; tertiary carboxamide; triazoles | antineoplastic agent; apoptosis inducer; EC 2.7.11.24 (mitogen-activated protein kinase) inhibitor |