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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

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

Nature communications, 2021-02, Vol.12 (1), p.819-17, Article 819 [Periódico revisado por pares]

England: Nature Publishing Group

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Título:
Cryo-EM structural analysis of FADD:Caspase-8 complexes defines the catalytic dimer architecture for co-ordinated control of cell fate
Autor: Fox, Joanna L ; Hughes, Michelle A ; Meng, Xin ; Sarnowska, Nikola A ; Powley, Ian R ; Jukes-Jones, Rebekah ; Dinsdale, David ; Ragan, Timothy J ; Fairall, Louise ; Schwabe, John W R ; Morone, Nobuhiro ; Cain, Kelvin ; MacFarlane, Marion
Assuntos: Apoptosis ; Binding sites ; c-FLIP protein ; CASP8 and FADD-Like Apoptosis Regulating Protein - chemistry ; CASP8 and FADD-Like Apoptosis Regulating Protein - genetics ; CASP8 and FADD-Like Apoptosis Regulating Protein - metabolism ; Caspase 8 - chemistry ; Caspase 8 - genetics ; Caspase 8 - metabolism ; Caspase-8 ; Catalytic Domain ; Cell death ; Cell fate ; Cloning, Molecular ; Cryoelectron Microscopy ; Death Domain Receptor Signaling Adaptor Proteins - chemistry ; Death Domain Receptor Signaling Adaptor Proteins - genetics ; Death Domain Receptor Signaling Adaptor Proteins - metabolism ; Dimerization ; Dimers ; Electron microscopy ; Elongation ; Escherichia coli - genetics ; Escherichia coli - metabolism ; FADD protein ; Fas-Associated Death Domain Protein - chemistry ; Fas-Associated Death Domain Protein - genetics ; Fas-Associated Death Domain Protein - metabolism ; FLIP protein ; Gene Expression ; Genetic Vectors - chemistry ; Genetic Vectors - metabolism ; HEK293 Cells ; Homeostasis ; Humans ; Models, Molecular ; Mortality ; Platforms ; Protein Binding ; Protein Conformation, alpha-Helical ; Protein Conformation, beta-Strand ; Protein Interaction Domains and Motifs ; Protein Isoforms - chemistry ; Protein Isoforms - genetics ; Protein Isoforms - metabolism ; Protein Multimerization ; Receptor-Interacting Protein Serine-Threonine Kinases - chemistry ; Receptor-Interacting Protein Serine-Threonine Kinases - genetics ; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism ; Recombinant Proteins - chemistry ; Recombinant Proteins - genetics ; Recombinant Proteins - metabolism ; Recruitment ; Regulated Cell Death - genetics ; Signaling ; Steric hindrance ; Structural analysis ; Tumor necrosis factor ; Tumor Necrosis Factor-alpha - chemistry ; Tumor Necrosis Factor-alpha - genetics ; Tumor Necrosis Factor-alpha - metabolism
É parte de: Nature communications, 2021-02, Vol.12 (1), p.819-17, Article 819
Descrição: 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.
Editor: England: Nature Publishing Group
Idioma: Inglês

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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

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

England: Nature Publishing Group

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