Stoichiometry of the CD95 Death-Inducing Signaling Complex: Experimental and Modeling Evidence for a Death Effector Domain Chain Model
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The CD95 (Fas/APO-1) death-inducing signaling complex (DISC) is essential for the initiation of CD95-mediated apoptotic and nonapoptotic responses. The CD95 DISC comprises CD95, FADD, procaspase-8, procaspase-10, and c-FLIP proteins. Procaspase-8 and procaspase-10 are activated at the DISC, leading to the formation of active caspases and apoptosis initiation. In this study we analyzed the stoichiometry of the CD95 DISC. Using quantitative western blots, mass spectrometry, and mathematical modeling, we reveal that the amount of DED proteins procaspase-8/procaspase-10 and c-FLIP at the DISC exceeds that of FADD by several-fold. Furthermore, our findings imply that procaspase-8, procaspase-10, and c-FLIP could form DED chains at the DISC, enabling the formation of dimers and efficient activation of caspase-8. Taken together, our findings provide an enhanced understanding of caspase-8 activation and initiation of apoptosis at the DISC.
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CASP8 maturation involves a cascade initiated by binding of CASP8 to FADD at DISC.
“In particular, CASP8 maturation involves a cascade of events initiated by the binding of CASP8 to FADD at the DISC.”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [293]
Binding of CASP8 to FADD enables assembly of a linear filament of CASP8 molecules that facilitates homodimerization and activation by autoproteolytic cleavage.
“This interaction enables the assembly of a linear filament of CASP8 molecules (depending on their DEDs) that facilitates homodimerization and consequent activation by autoproteolytic cleavage [291–295].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [293]
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- Authors
- Schleich, K., Warnken, U., Fricker, N., Öztürk, S., Richter, P., Kammerer, K., Schnölzer, M., Krammer, P. H., & Lavrik, I. N.
- Affiliations
- German Cancer Research Center (DE)
- Corresponding author
- Lavrik, Inna N.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2012-07
- Volume
- 47
- Issue
- 2
- Pages
- 306-319
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2142525393
- Cited by
- 198
- References
- 68
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 7 · 2023: 3 · 2022: 11 · 2021: 17 · 2020: 14 · 2019: 15 · 2018: 13 · 2017: 14 · 2016: 22 · 2015: 22 · 2014: 27 · 2013: 17 · 2012: 5
- FWCI
- 9.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- Fas, Fas/APO-1, death-inducing signaling complex, death effector domain, procaspase-8, c-FLIP, FADD, caspase-8 activation, mathematical modeling of signaling
- MeSH terms
- HeLa Cells, Humans, Microscopy, Fluorescence, Models, Biological, Models, Theoretical, Mass Spectrometry, Signal Transduction, Apoptosis, fas Receptor, Dimerization, Caspase 8, Fas-Associated Death Domain Protein, Death Domain Receptor Signaling Adaptor Proteins, Caspase 10
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