Co-operative and hierarchical binding of c-FLIP and caspase-8

• Verfasst von: Hughes, Michelle A. [VerfasserIn]
• Verfasst von: 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
• DOI: doi:10.1016/j.molcel.2016.02.023
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1588186881

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.