Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/38064
Title: Co-operative and Hierarchical Binding of c-FLIP and Caspase-8: A Unified Model Defines How c-FLIP Isoforms Differentially Control Cell Fate
Authors: Hughes, Michelle A.
Powley, Ian R.
Jukes-Jones, Rebekah
Horn, Sebastian
Feoktistova, Maria
Fairall, Louise
Schwabe, John W. R.
Leverkus, Martin
Cain, Kelvin
MacFarlane, Marion
First Published: 17-Mar-2016
Publisher: Elsevier (Cell Press)
Citation: Molecular Cell, 2016, 61 (6), pp. 834-849
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 Link: 10.1016/j.molcel.2016.02.023
ISSN: 1097-2765
eISSN: 1097-4164
Links: http://www.sciencedirect.com/science/article/pii/S1097276516001349
http://hdl.handle.net/2381/38064
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2016. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Appears in Collections:Published Articles, Dept. of Molecular and Cell Biology

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