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Cryo-EM structural analysis of FADD:Caspase-8 complexes defines the catalytic dimer architecture for co-ordinated control of cell fate by Fox, Joanna L. (author);Hughes, Michelle A. (author);Meng, Xin (author);Sarnowska, Nikola A. (author);Powley, Ian R. (author);Jukes-Jones, Rebekah (author);Dinsdale, David (author);Ragan, Timothy J. (author);Fairall, Louise (author);Schwabe, John W. R. (author);Morone, Nobuhiro (author);Cain, Kelvin (author);MacFarlane, Marion (author) is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.

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## 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-FLIP~S~ 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.

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Author

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

Publisher

Springer Science and Business Media LLC

Published

2021

Language

EN

Field

Biochemistry, Genetics and Molecular Biology (Life Sciences)