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-Structure paper
Title | Cryo-EM Structure of Caspase-8 Tandem DED Filament Reveals Assembly and Regulation Mechanisms of the Death-Inducing Signaling Complex. |
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Journal, issue, pages | Mol Cell, Vol. 64, Issue 2, Page 236-250, Year 2016 |
Publish date | Oct 20, 2016 |
Authors | 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 / Katryn J Stacey / Edward H Egelman / Hao Wu / |
PubMed 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 ...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. |
External links | Mol Cell / PubMed:27746017 / PubMed Central |
Methods | EM (helical sym.) / X-ray diffraction |
Resolution | 3.157 - 4.6 Å |
Structure data | EMDB-8300: Cryo-EM structure of Casp-8 tDED filament (CASP target) PDB-5jqe: |
Source |
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Keywords | HYDROLASE / apoptosis / Casp-8 / filament / DED / Death domain |