Co-operative and hierarchical binding of c-FLIP and caspase-8: a unified model defines how c-FLIP isoforms differentially control cell fate
The death-inducing signaling complex (DISC) initiates death receptor-induced apoptosis. DISC assembly and activation are controlled by c-FLIP isoforms, which function as pro-apoptotic (c-FLIPL only) or anti-apoptotic (c-FLIPL/c-FLIPS) regulators of procaspase-8 activation. Current models assume that...
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| Hauptverfasser: | , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
March 17, 2016
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| In: |
Molecular cell
Year: 2016, Jahrgang: 61, Heft: 6, Pages: 834-849 |
| ISSN: | 1097-4164 |
| DOI: | 10.1016/j.molcel.2016.02.023 |
| Online-Zugang: | Verlag, Volltext: http://dx.doi.org/10.1016/j.molcel.2016.02.023 Verlag, Volltext: http://www.sciencedirect.com/science/article/pii/S1097276516001349 
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| Verfasserangaben: | Michelle A. Hughes, Ian R. Powley, Rebekah Jukes-Jones, Sebastian Horn, Maria Feoktistova, Louise Fairall, John W.R. Schwabe, Martin Leverkus, Kelvin Cain, and Marion MacFarlane |
| Zusammenfassung: | The death-inducing signaling complex (DISC) initiates death receptor-induced apoptosis. DISC assembly and activation are controlled by c-FLIP isoforms, which function as pro-apoptotic (c-FLIPL only) or anti-apoptotic (c-FLIPL/c-FLIPS) regulators of procaspase-8 activation. Current models assume that c-FLIP directly competes with procaspase-8 for recruitment to FADD. Using a functional reconstituted DISC, structure-guided mutagenesis, and quantitative LC-MS/MS, we show that c-FLIPL/S binding to the DISC is instead a co-operative procaspase-8-dependent process. FADD initially recruits procaspase-8, which in turn recruits and heterodimerizes with c-FLIPL/S via a hierarchical binding mechanism. Procaspase-8 activation is regulated by the ratio of unbound c-FLIPL/S to procaspase-8, which determines composition of the procaspase-8:c-FLIPL/S heterodimer. Thus, procaspase-8:c-FLIPL exhibits localized enzymatic activity and is preferentially an activator, promoting DED-mediated procaspase-8 oligomer assembly, whereas procaspase-8:c-FLIPS lacks activity and potently blocks procaspase-8 activation. This co-operative hierarchical binding model explains the dual role of c-FLIPL and crucially defines how c-FLIP isoforms differentially control cell fate. |
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| Beschreibung: | Gesehen am 27.02.2019 |
| Beschreibung: | Online Resource |
| ISSN: | 1097-4164 |
| DOI: | 10.1016/j.molcel.2016.02.023 |