Cited by 198Cell death mechanisms and regulationInflammasome and immune disordersEnzyme Structure and Function

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Cryo-EM Structure of Caspase-8 Tandem DED Filament Reveals Assembly and Regulation Mechanisms of the Death-Inducing Signaling Complex

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Fu, Tian-Min, Li, Yang, Lu, Alvin, Li, Zongli, Vajjhala, Parimala R., Cruz, Anthony C., Srivastava, Devendra B., DiMaio, Frank, Penczek, Pawel A., Siegel, Richard M., Stacey, Katryn J., Egelman, Edward H., Wu, Hao·2016·Molecular Cell

DOI 10.1016/j.molcel.2016.09.009PMC PMC5089849

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Abstract

Caspase-8 activation can be triggered by death receptor-mediated formation of the death-inducing signaling complex (DISC) and by the inflammasome adaptor ASC. Caspase-8 assembles with FADD at the DISC and with ASC at the inflammasome through its tandem death effector domain (tDED), which is regulated by the tDED-containing cellular inhibitor cFLIP and the viral inhibitor MC159. Here we present the caspase-8 tDED filament structure determined by cryoelectron microscopy. Extensive assembly interfaces not predicted by the previously proposed linear DED chain model were uncovered, and were further confirmed by structure-based mutagenesis in filament formation in vitro and Fas-induced apoptosis and ASC-mediated caspase-8 recruitment in cells. Structurally, the two DEDs in caspase-8 use quasi-equivalent contacts to enable assembly. Using the tDED filament structure as a template, structural analyses reveal the interaction surfaces between FADD and caspase-8 and the distinct mechanisms of regulation by cFLIP and MC159 through comingling and capping, respectively.

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Authors: Fu, T.-M., Li, Y., Lu, A., Li, Z., Vajjhala, P. R., Cruz, A. C., Srivastava, D. B., DiMaio, F., Penczek, P. A., Siegel, R. M., Stacey, K. J., Egelman, E. H., & Wu, H.
Affiliations: Boston Children's Hospital (US)
Howard Hughes Medical Institute (US)
The University of Queensland (AU)
National Institutes of Health (US)
University of Washington (US)
Texas Medical Center (US)
University of Virginia (US)
Corresponding author: Wu, Hao
ORCID: Fu, Tian-Min
Li, Yang
Lu, Alvin
Li, Zongli
Vajjhala, Parimala R.
Cruz, Anthony C.
DiMaio, Frank
Penczek, Pawel A.
Siegel, Richard M.
Stacey, Katryn J.
Egelman, Edward H.
Wu, Hao
Venue: Molecular Cell
Publisher: Elsevier BV
Published: 2016-10
Volume: 64
Issue: 2
Pages: 236-250
ISSN: 1097-2765 (ISSN-L)
DOI: 10.1016/j.molcel.2016.09.009
PMC: PMC5089849
OpenAlex: W2531084658
Cited by: 196
References: 48
Citations by year: 2026: 16 · 2025: 22 · 2024: 24 · 2023: 9 · 2022: 16 · 2021: 35 · 2020: 25 · 2019: 24 · 2018: 13 · 2017: 10 · 2016: 1
FWCI: 8.49
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 384 d)
Locations: Molecular Cell (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health
National Health and Medical Research Council
National Medical Research Council
National Institute of General Medical Sciences (R01GM060635)
National Institute of Allergy and Infectious Diseases (R37AI050872, R01AI045937, R01AI124491)
National Institute of Biomedical Imaging and Bioengineering (R01EB001567)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (DP1HD087988)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
Keywords: caspase-8, death-inducing signaling complex, FADD, c-FLIP, ASC, inflammasome, death receptor signaling, caspase activation, protein filament assembly, protein-protein interfaces, Fas-mediated apoptosis, caspase inhibition
MeSH terms: Death Effector Domain, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Amino Acid Sequence, Binding Sites, Cytoskeletal Proteins, Humans, Plasmids, Protein Binding, Recombinant Fusion Proteins, Transfection, Viral Proteins, Gene Expression, Sequence Alignment, Apoptosis, Sequence Homology, Amino Acid, fas Receptor, Jurkat Cells, Cryoelectron Microscopy, Caspase 8, Fas-Associated Death Domain Protein, Death Domain Receptor Signaling Adaptor Proteins, CASP8 and FADD-Like Apoptosis Regulating Protein, CARD Signaling Adaptor Proteins, Protein Interaction Domains and Motifs

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Cryo-EM Structure of Caspase-8 Tandem DED Filament Reveals Assembly and Regulation Mechanisms of the Death-Inducing Signaling Complex

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