Differential affinity of FLIP and procaspase 8 for FADD’s DED binding surfaces regulates DISC assembly
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Death receptor activation triggers recruitment of FADD, which via its death effector domain (DED) engages the DEDs of procaspase 8 and its inhibitor FLIP to form death-inducing signalling complexes (DISCs). The DEDs of FADD, FLIP and procaspase 8 interact with one another using two binding surfaces defined by α1/α4 and α2/α5 helices, respectively. Here we report that FLIP has preferential affinity for the α1/α4 surface of FADD, whereas procaspase 8 has preferential affinity for FADD's α2/α5 surface. These relative affinities contribute to FLIP being recruited to the DISC at comparable levels to procaspase 8 despite lower cellular expression. Additional studies, including assessment of DISC stoichiometry and functional assays, suggest that following death receptor recruitment, the FADD DED preferentially engages FLIP using its α1/α4 surface and procaspase 8 using its α2/α5 surface; these tripartite intermediates then interact via the α1/α4 surface of FLIP DED1 and the α2/α5 surface of procaspase 8 DED2.
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c-FLIP isoforms and CASP8 are recruited at DISC to comparable levels.
“c-FLIP isoforms and CASP8 seem to be recruited at the DISC to comparable levels [303]”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [303]
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- Authors
- Majkut, J., Sgobba, M., Holohan, C., Crawford, N., Logan, A. E., Kerr, E., Higgins, C. A., Redmond, K. L., Riley, J. S., Stasik, I., Fennell, D. A., Van Schaeybroeck, S., Haider, S., Johnston, P. G., Haigh, D., & Longley, D. B.
- Affiliations
- Queen's University Belfast (GB)
- Corresponding author
- Longley, D. B.
- ORCID
- Venue
- Nature Communications
- Published
- 2014-02-28
- Volume
- 5
- Issue
- 1
- Pages
- 3350-3350
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC3942653
- OpenAlex
- W2093916833
- Cited by
- 81
- References
- 41
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 14 · 2023: 2 · 2022: 7 · 2021: 7 · 2020: 10 · 2019: 4 · 2018: 7 · 2017: 6 · 2016: 8 · 2015: 9 · 2014: 1
- FWCI
- 3.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- CLOK (University of Central Lancashire) (acceptedVersion)
- Hope's Institutional Research Archive (Liverpool Hope University) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Hope's Institutional Research Archive (Liverpool Hope University) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Research Portal (Queen's University Belfast) (submittedVersion)
- Funders
- Amgen
- Wellcome Trust (099470)
- Invest Northern Ireland
- Cancer Research UK (13172, 13721)
- Public Health Agency (RRG/3261/05)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- c-FLIP, procaspase-8, FADD, death effector domain, death-inducing signalling complex, death receptor signaling, protein-protein binding affinity, apoptosis
- MeSH terms
- Chromatography, Gel, Humans, Protein Binding, Blotting, Western, HCT116 Cells, Immunoprecipitation, Caspase 8, Fas-Associated Death Domain Protein, CASP8 and FADD-Like Apoptosis Regulating Protein
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