Crystal structure of the death effector domains of caspase-8

2015 ◽  
Vol 463 (3) ◽  
pp. 297-302 ◽  
Author(s):  
Chen Shen ◽  
Hong Yue ◽  
Jianwen Pei ◽  
Xiaomin Guo ◽  
Tao Wang ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Caspase 8 ◽  
Effector Domains ◽  
Death Effector

scholarly journals Crystal structure of caspase recruiting domain (CARD) of apoptosis repressor with CARD (ARC) and its implication in inhibition of apoptosis

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Tae-ho Jang ◽  
Seong Hyun Kim ◽  
Jae-Hee Jeong ◽  
Sunghwan Kim ◽  
Yeon-Gil Kim ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Death Domain ◽  
Apoptosis Pathway ◽  
Effector Domains ◽  
Inhibitory Function ◽  
Rich Domain ◽  
Extrinsic Apoptosis ◽  
Optimal Target ◽  
Death Effector ◽  
Disc Formation

Abstract Apoptosis repressor with caspase recruiting domain (ARC) is a multifunctional inhibitor of apoptosis that is unusually over-expressed or activated in various cancers and in the state of the pulmonary hypertension. Therefore, ARC might be an optimal target for therapeutic intervention. Human ARC is composed of two distinct domains, N-terminal caspase recruiting domain (CARD) and C-terminal P/E (proline and glutamic acid) rich domain. ARC inhibits the extrinsic apoptosis pathway by interfering with DISC formation. ARC CARD directly interacts with the death domains (DDs) of Fas and FADD, as well as with the death effector domains (DEDs) of procaspase-8. Here, we report the first crystal structure of the CARD domain of ARC at a resolution of 2.4 Å. Our structure was a dimer with novel homo-dimerization interfaces that might be critical to its inhibitory function. Interestingly, ARC did not exhibit a typical death domain fold. The sixth helix (H6), which was detected at the typical death domain fold, was not detected in the structure of ARC, indicating that H6 may be dispensable for the function of the death domain superfamily.

scholarly journals The Death Effector Domains of Caspase-8 Induce Terminal Differentiation

PLoS ONE ◽  
2009 ◽  
Vol 4 (11) ◽  
pp. e7879 ◽  
Author(s):  
Ainhoa Mielgo ◽  
Vicente A. Torres ◽  
Michael C. Schmid ◽  
Ryon Graf ◽  
Samantha G. Zeitlin ◽  
...  
Keyword(s):  
Terminal Differentiation ◽  
Caspase 8 ◽  
Effector Domains ◽  
Death Effector

scholarly journals The Death Effector Domains (DEDs) of the Molluscum Contagiosum Virus MC159 v-FLIP Protein Are Not Functionally Interchangeable with Each Other or with the DEDs of Caspase-8

Virology ◽  
2002 ◽  
Vol 300 (2) ◽  
pp. 217-225 ◽  
Author(s):  
Tara L. Garvey ◽  
John Bertin ◽  
Richard M. Siegel ◽  
Michael J. Lenardo ◽  
Jeffrey I. Cohen
Keyword(s):  
Molluscum Contagiosum ◽  
Caspase 8 ◽  
Molluscum Contagiosum Virus ◽  
Effector Domains ◽  
Death Effector

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

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Joanna L. Fox ◽  
Michelle A. Hughes ◽  
Xin Meng ◽  
Nikola A. Sarnowska ◽  
Ian R. Powley ◽  
...  
Keyword(s):  
Cell Death ◽  
Structural Analysis ◽  
Cell Fate ◽  
Catalytic Domain ◽  
Caspase 8 ◽  
Type I ◽  
Signaling Complex ◽  
Catalytic Domains ◽  
Regulated Cell Death ◽  
Death Effector

AbstractRegulated 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.

scholarly journals The pseudokinase MLKL activates PAD4-dependent NET formation in necroptotic neutrophils

2018 ◽  
Vol 11 (546) ◽  
pp. eaao1716 ◽  
Author(s):  
Akshay A. D’Cruz ◽  
Mary Speir ◽  
Meghan Bliss-Moreau ◽  
Sylvia Dietrich ◽  
Shu Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Kinase Domain ◽  
Neutrophil Extracellular Trap ◽  
Human Neutrophils ◽  
Caspase 8 ◽  
Interacting Protein ◽  
Dependent Activity ◽  
Mrsa Infection ◽  
Death Effector ◽  
Net Release

Neutrophil extracellular trap (NET) formation can generate short-term, functional anucleate cytoplasts and trigger loss of cell viability. We demonstrated that the necroptotic cell death effector mixed lineage kinase domain–like (MLKL) translocated from the cytoplasm to the plasma membrane and stimulated downstream NADPH oxidase–independent ROS production, loss of cytoplasmic granules, breakdown of the nuclear membrane, chromatin decondensation, histone hypercitrullination, and extrusion of bacteriostatic NETs. This process was coordinated by receptor-interacting protein kinase-1 (RIPK1), which activated the caspase-8–dependent apoptotic or RIPK3/MLKL-dependent necroptotic death of mouse and human neutrophils. Genetic deficiency of RIPK3 and MLKL prevented NET formation but did not prevent cell death, which was because of residual caspase-8–dependent activity. Peptidylarginine deiminase 4 (PAD4) was activated downstream of RIPK1/RIPK3/MLKL and was required for maximal histone hypercitrullination and NET extrusion. This work defines a distinct signaling network that activates PAD4-dependent NET release for the control of methicillin-resistant Staphylococcus aureus (MRSA) infection.

Covalent inhibition revealed by the crystal structure of the caspase-8/p35 complex

Nature ◽  
2001 ◽  
Vol 410 (6827) ◽  
pp. 494-497 ◽  
Author(s):  
Guozhou Xu ◽  
Maurizio Cirilli ◽  
Yihua Huang ◽  
Rebecca L. Rich ◽  
David G. Myszka ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Caspase 8 ◽  
Covalent Inhibition

scholarly journals Paclitaxel promotes a caspase 8-mediated apoptosis through death effector domain association with microtubules

Oncogene ◽  
2009 ◽  
Vol 28 (40) ◽  
pp. 3551-3562 ◽  
Author(s):  
A Mielgo ◽  
V A Torres ◽  
K Clair ◽  
S Barbero ◽  
D G Stupack
Keyword(s):  
Caspase 8 ◽  
Effector Domain ◽  
Death Effector Domain ◽  
Death Effector

scholarly journals Caspases: the executioners of apoptosis

1997 ◽  
Vol 326 (1) ◽  
pp. 1-16 ◽  
Author(s):  
Gerald M. COHEN
Keyword(s):  
Cell Death ◽  
Morphological Changes ◽  
Cysteine Proteases ◽  
Death Receptors ◽  
Small Subunit ◽  
Caspase 8 ◽  
Death Domain ◽  
Interacting Protein ◽  
Death Effector ◽  
Caspase 2

Apoptosis is a major form of cell death, characterized initially by a series of stereotypic morphological changes. In the nematode Caenorhabditis elegans, the gene ced-3 encodes a protein required for developmental cell death. Since the recognition that CED-3 has sequence identity with the mammalian cysteine protease interleukin-1β-converting enzyme (ICE), a family of at least 10 related cysteine proteases has been identified. These proteins are characterized by almost absolute specificity for aspartic acid in the P1 position. All the caspases (ICE-like proteases) contain a conserved QACXG (where X is R, Q or G) pentapeptide active-site motif. Caspases are synthesized as inactive proenzymes comprising an N-terminal peptide (prodomain) together with one large and one small subunit. The crystal structures of both caspase-1 and caspase-3 show that the active enzyme is a heterotetramer, containing two small and two large subunits. Activation of caspases during apoptosis results in the cleavage of critical cellular substrates, including poly(ADP-ribose) polymerase and lamins, so precipitating the dramatic morphological changes of apoptosis. Apoptosis induced by CD95 (Fas/APO-1) and tumour necrosis factor activates caspase-8 (MACH/FLICE/Mch5), which contains an N-terminus with FADD (Fas-associating protein with death domain)-like death effector domains, so providing a direct link between cell death receptors and the caspases. The importance of caspase prodomains in the regulation of apoptosis is further highlighted by the recognition of adapter molecules, such as RAIDD [receptor-interacting protein (RIP)-associated ICH-1/CED-3-homologous protein with a death domain]/CRADD (caspase and RIP adapter with death domain), which binds to the prodomain of caspase-2 and recruits it to the signalling complex. Cells undergoing apoptosis following triggering of death receptors execute the death programme by activating a hierarchy of caspases, with caspase-8 and possibly caspase-10 being at or near the apex of this apoptotic cascade.

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