Please use this identifier to cite or link to this item:
Title: A death effector domain chain DISC model reveals a crucial role for caspase-8 chain assembly in mediating apoptotic cell death.
Authors: Dickens, LS
Boyd, RS
Jukes-Jones, R
Hughes, MA
Robinson, GL
Fairall, L
Schwabe, JW
Cain, K
Macfarlane, M
First Published: 27-Jul-2012
Citation: MOL CELL, 2012, 47 (2), pp. 291-305
Abstract: Formation of the death-inducing signaling complex (DISC) is a critical step in death receptor-mediated apoptosis, yet the mechanisms underlying assembly of this key multiprotein complex remain unclear. Using quantitative mass spectrometry, we have delineated the stoichiometry of the native TRAIL DISC. While current models suggest that core DISC components are present at a ratio of 1:1, our data indicate that FADD is substoichiometric relative to TRAIL-Rs or DED-only proteins; strikingly, there is up to 9-fold more caspase-8 than FADD in the DISC. Using structural modeling, we propose an alternative DISC model in which procaspase-8 molecules interact sequentially, via their DED domains, to form a caspase-activating chain. Mutating key interacting residues in procaspase-8 DED2 abrogates DED chain formation in cells and disrupts TRAIL/CD95 DISC-mediated procaspase-8 activation in a functional DISC reconstitution model. This provides direct experimental evidence for a DISC model in which DED chain assembly drives caspase-8 dimerization/activation, thereby triggering cell death.
DOI Link: 10.1016/j.molcel.2012.05.004
eISSN: 1097-4164
Type: Journal Article
Appears in Collections:Published Articles, Dept. of Biochemistry

Files in This Item:
There are no files associated with this item.

Items in LRA are protected by copyright, with all rights reserved, unless otherwise indicated.