| Online-Ressource |
Verfasst von: | Hughes, Michelle A. [VerfasserIn]  |
| Horn, Sebastian [VerfasserIn]  |
Titel: | Co-operative and hierarchical binding of c-FLIP and caspase-8 |
Titelzusatz: | a unified model defines how c-FLIP isoforms differentially control cell fate |
Verf.angabe: | 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 |
E-Jahr: | 2016 |
Jahr: | March 17, 2016 |
Umfang: | 16 S. |
Fussnoten: | Gesehen am 27.02.2019 |
Titel Quelle: | Enthalten in: Molecular cell |
Ort Quelle: | [Cambridge, Mass.] : Cell Press, 1997 |
Jahr Quelle: | 2016 |
Band/Heft Quelle: | 61(2016), 6, Seite 834-849 |
ISSN Quelle: | 1097-4164 |
Abstract: | 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. |
DOI: | doi:10.1016/j.molcel.2016.02.023 |
URL: | Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.
Volltext: http://dx.doi.org/10.1016/j.molcel.2016.02.023 |
| Volltext: http://www.sciencedirect.com/science/article/pii/S1097276516001349 |
| DOI: https://doi.org/10.1016/j.molcel.2016.02.023 |
Datenträger: | Online-Ressource |
Sprache: | eng |
K10plus-PPN: | 1588186881 |
Verknüpfungen: | → Zeitschrift |
Co-operative and hierarchical binding of c-FLIP and caspase-8 / Hughes, Michelle A. [VerfasserIn]; March 17, 2016 (Online-Ressource)