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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.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Hughes, Michelle A 
Meng, Xin 
Sarnowska, Nikola A 
Powley, Ian R 

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.

Description

Keywords

CASP8 and FADD-Like Apoptosis Regulating Protein, Caspase 8, Catalytic Domain, Cloning, Molecular, Cryoelectron Microscopy, Death Domain Receptor Signaling Adaptor Proteins, Escherichia coli, Fas-Associated Death Domain Protein, Gene Expression, Genetic Vectors, HEK293 Cells, Humans, Models, Molecular, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Protein Isoforms, Protein Multimerization, Receptor-Interacting Protein Serine-Threonine Kinases, Recombinant Proteins, Regulated Cell Death, Tumor Necrosis Factor-alpha

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

12

Publisher

Springer Science and Business Media LLC