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Title | Cryo-EM structural analysis of FADD:Caspase-8 complexes defines the catalytic dimer architecture for co-ordinated control of cell fate. |
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Journal, issue, pages | Nat Commun, Vol. 12, Issue 1, Page 819, Year 2021 |
Publish date | Feb 5, 2021 |
Authors | 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 / Marion MacFarlane / |
PubMed 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: ...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 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. |
External links | Nat Commun / PubMed:33547302 / PubMed Central |
Methods | EM (single particle) |
Resolution | 12.0 - 22.41 Å |
Structure data | EMDB-11938: EMDB-11939: EMDB-11940: EMDB-11941: |
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