Cryo-EM structure of caspase-8 tandem DED filament reveals assembly and regulation mechanisms of the death-inducing signaling complex

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. and Wu, Hao (2016) Cryo-EM structure of caspase-8 tandem DED filament reveals assembly and regulation mechanisms of the death-inducing signaling complex. Molecular Cell, 64 2: 236-250. doi:10.1016/j.molcel.2016.09.009


Author 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
Title Cryo-EM structure of caspase-8 tandem DED filament reveals assembly and regulation mechanisms of the death-inducing signaling complex
Journal name Molecular Cell   Check publisher's open access policy
ISSN 1097-2765
1097-4164
Publication date 2016-10-20
Sub-type Article (original research)
DOI 10.1016/j.molcel.2016.09.009
Open Access Status Not yet assessed
Volume 64
Issue 2
Start page 236
End page 250
Total pages 16
Place of publication Cambridge, MA, United States
Publisher Cell Press
Language eng
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.
Keyword DED
DISC
FADD
Fas
MC159
cFLIP
caspase-8
death domain
filament
vFLIP
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID R01 AI124491
DP1 HD087988
R01 GM060635
R01 EB001567
R37 AI050872
R01 AI045937
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
School of Chemistry and Molecular Biosciences
Institute for Molecular Bioscience - Publications
 
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Created: Thu, 10 Nov 2016, 01:30:45 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences