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Structure of the apoptosome: mechanistic insights into activation of an initiator caspase from Drosophila.
- Source :
-
Genes & development [Genes Dev] 2015 Feb 01; Vol. 29 (3), pp. 277-87. - Publication Year :
- 2015
-
Abstract
- Apoptosis is executed by a cascade of caspase activation. The autocatalytic activation of an initiator caspase, exemplified by caspase-9 in mammals or its ortholog, Dronc, in fruit flies, is facilitated by a multimeric adaptor complex known as the apoptosome. The underlying mechanism by which caspase-9 or Dronc is activated by the apoptosome remains unknown. Here we report the electron cryomicroscopic (cryo-EM) structure of the intact apoptosome from Drosophila melanogaster at 4.0 Å resolution. Analysis of the Drosophila apoptosome, which comprises 16 molecules of the Dark protein (Apaf-1 ortholog), reveals molecular determinants that support the assembly of the 2.5-MDa complex. In the absence of dATP or ATP, Dronc zymogen potently induces formation of the Dark apoptosome, within which Dronc is efficiently activated. At 4.1 Å resolution, the cryo-EM structure of the Dark apoptosome bound to the caspase recruitment domain (CARD) of Dronc (Dronc-CARD) reveals two stacked rings of Dronc-CARD that are sandwiched between two octameric rings of the Dark protein. The specific interactions between Dronc-CARD and both the CARD and the WD40 repeats of a nearby Dark protomer are indispensable for Dronc activation. These findings reveal important mechanistic insights into the activation of initiator caspase by the apoptosome.<br /> (© 2015 Pang et al.; Published by Cold Spring Harbor Laboratory Press.)
Details
- Language :
- English
- ISSN :
- 1549-5477
- Volume :
- 29
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Genes & development
- Publication Type :
- Academic Journal
- Accession number :
- 25644603
- Full Text :
- https://doi.org/10.1101/gad.255877.114