Cryo-EM structural analysis of FADD:Caspase-8 complexes defines the catalytic dimer architecture for co-ordinated control of cell fate

Joanna L. Fox (), Michelle A. Hughes, Xin Meng, Nikola A. Sarnowska, Ian R. Powley, Rebekah Jukes-Jones, David Dinsdale, Timothy J. Ragan, Louise Fairall, John W. R. Schwabe, Nobuhiro Morone, Kelvin Cain and Marion MacFarlane ()
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Joanna L. Fox: University of Cambridge
Michelle A. Hughes: University of Cambridge
Xin Meng: University of Cambridge
Nikola A. Sarnowska: University of Cambridge
Ian R. Powley: University of Cambridge
Rebekah Jukes-Jones: University of Cambridge
David Dinsdale: University of Cambridge
Timothy J. Ragan: University of Leicester
Louise Fairall: University of Leicester
John W. R. Schwabe: University of Leicester
Nobuhiro Morone: University of Cambridge
Kelvin Cain: University of Cambridge
Marion MacFarlane: University of Cambridge

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Regulated cell death is essential in development and cellular homeostasis. Multi-protein platforms, including the Death-Inducing Signaling Complex (DISC), co-ordinate cell fate via a core FADD:Caspase-8 complex and its regulatory partners, such as the cell death inhibitor c-FLIP. Here, using electron microscopy, we visualize full-length procaspase-8 in complex with FADD. Our structural analysis now reveals how the FADD-nucleated tandem death effector domain (tDED) helical filament is required to orientate the procaspase-8 catalytic domains, enabling their activation via anti-parallel dimerization. Strikingly, recruitment of c-FLIPS into this complex inhibits Caspase-8 activity by altering tDED triple helix architecture, resulting in steric hindrance of the canonical tDED Type I binding site. This prevents both Caspase-8 catalytic domain assembly and tDED helical filament elongation. Our findings reveal how the plasticity, composition and architecture of the core FADD:Caspase-8 complex critically defines life/death decisions not only via the DISC, but across multiple key signaling platforms including TNF complex II, the ripoptosome, and RIPK1/RIPK3 necrosome.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20806-9

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DOI: 10.1038/s41467-020-20806-9

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