Evidence map›Paper›PMID 27746017›Full record

ArticleMolecular cell2016

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

Tian-Min Fu, Yang Li, Alvin Lu, Zongli Li, Parimala R Vajjhala, Anthony C Cruz, Devendra B Srivastava, Frank DiMaio, Pawel A Penczek, Richard M Siegel and 3 more

Open access · bronzeAbstract read
In one paragraph

Article in Molecular cell, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 113 papers.

0numbers the graph read from it
0cells of the map it votes in
113citing papers in PubMed
8.4field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

113 citing papers in PubMed, 186 citations in OpenAlex.

  1. Article
  2. Article
  3. Review
  4. Article
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  8. Article
  9. Review
  10. Article
  11. Review
  12. Article
  13. PANoptosis: A novel therapeutic target in kidney disease (Review).International journal of molecular medicine · 2025
    Review
  14. Article
  15. Article
  16. Review
  17. Proceedings of the National Academy of Sciences of the United States of America · 2025
    Article
  18. Assembly and activation of the death-inducing signaling complex.Proceedings of the National Academy of Sciences of the United States of America · 2025
    Article
  19. Article
  20. Review

53 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

13 authors at 7 institutions in 2 countries.

Tian-Min FuDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
Yang LiDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
Alvin LuDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
Zongli LiDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
Parimala R VajjhalaSchool of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD 4072, Australia.
Anthony C CruzAutoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD 20892, USA.
Devendra B SrivastavaDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
Frank DiMaioDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Pawel A PenczekDepartment of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, TX 77030, USA.
Richard M SiegelAutoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD 20892, USA.
Katryn J StaceySchool of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD 4072, Australia; Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia.
Edward H EgelmanDepartment of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA.
Hao WuDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address: wu@crystal.harvard.edu.
Boston Children's Hospital · USNational Institute of Arthritis and Musculoskeletal and Skin Diseases · USThe University of Queensland · AUHoward Hughes Medical Institute · USThe University of Texas Health Science Center at Houston · USUniversity of Virginia · USUniversity of Washington · US

Funding

TNF-receptors and programmed cell death in regulation of autoimmunityZIAAR041133 · NIAMS · NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES · PI SIEGEL, RICHARD M · 2009 to 2019
$9.3M
Structural Studies of TNF Receptor Associated Factors (TRAFs)R01AI045937 · NIAID · WEILL MEDICAL COLL OF CORNELL UNIV · PI WU, HAO · 1999 to 2016
$5.9M
NLRP1 and CARD8 Inflammasomes: Assembly, Regulation and Stress SensingR01AI124491 · NIAID · BOSTON CHILDREN'S HOSPITAL · PI WU, HAO · 2016 to 2025
$5.1M
Structural & Functional Studies of TLR/IL-1R SignalingR37AI050872 · NIAID · BOSTON CHILDREN'S HOSPITAL · PI WU, HAO · 2012 to 2021
$4.7M
SMOCs: Novel Signal Transduction Complexes as New Targets for Drug DiscoveryDP1HD087988 · NICHD · BOSTON CHILDREN'S HOSPITAL · PI WU, HAO · 2015 to 2019
$4.4M
HIGH RESOLUTION IN SINGLE PARTICLE RECONSTRUCTIONR01GM060635 · NIGMS · WADSWORTH CENTER · PI PENCZEK, PAWEL A. · 2000 to 2016
$4.3M
Methods for the Analysis of Helical Macromolecular ComplexesR01EB001567 · NIBIB · UNIVERSITY OF VIRGINIA CHARLOTTESVILLE · PI EGELMAN, EDWARD H. · 2003 to 2014
$3.6M
NIAID NIH HHS R01 AI045937NIAID NIH HHS R01 AI124491NIAID NIH HHS R37 AI050872NIBIB NIH HHS R01 EB001567NICHD NIH HHS DP1 HD087988NIGMS NIH HHS R01 GM060635
6 · The paper itself

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.

Indexed as

Amino Acid SequenceApoptosisBinding SitesCARD Signaling Adaptor ProteinsCASP8 and FADD-Like Apoptosis Regulating ProteinCaspase 8Cryoelectron MicroscopyCytoskeletal ProteinsDeath Domain Receptor Signaling Adaptor ProteinsDeath Effector DomainFas-Associated Death Domain Proteinfas ReceptorGene ExpressionHumansJurkat CellsPlasmidsCARD Signaling Adaptor ProteinsCASP8 and FADD-Like Apoptosis Regulating ProteinCASP8 protein, humanCaspase 8Cytoskeletal ProteinsDeath Domain Receptor Signaling Adaptor ProteinsFADD protein, humanFas-Associated Death Domain ProteinFAS protein, humanfas ReceptorPYCARD protein, humanRecombinant Fusion Proteinsviral FLIP protein, Molluscum contagiosum virusViral Proteinscaspase-8cFLIPdeath domainDEDDISCFADDFasfilamentMC159vFLIP

Identifiers

PMID27746017
PMCPMC5089849
OpenAlexW2531084658

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.