Cryo-EM Structure of Caspase-8 Tandem DED Filament Reveals Assembly and Regulation Mechanisms of the Death-Inducing Signaling Complex.
Mol Cell
; 64(2): 236-250, 2016 10 20.
Article
in En
| MEDLINE
| ID: mdl-27746017
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Viral Proteins
/
Caspase 8
/
Death Domain Receptor Signaling Adaptor Proteins
/
CASP8 and FADD-Like Apoptosis Regulating Protein
/
Fas-Associated Death Domain Protein
Type of study:
Prognostic_studies
Language:
En
Journal:
Mol Cell
Year:
2016
Document type:
Article