Structure of the apoptosome: Mechanistic insights into activation of an initiator caspase from Drosophila

Yuxuan Pang, Xiao Chen Bai, Chuangye Yan, Qi Hao, Zheqin Chen, Jia Wei Wang, Sjors H.W. Scheres, Yigong Shi

Research output: Contribution to journalArticle

31 Scopus citations

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 4.1Å 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.

Original languageEnglish (US)
Pages (from-to)277-287
Number of pages11
JournalGenes and Development
Volume29
Issue number3
DOIs
StatePublished - Jan 1 2015

Keywords

  • Apoptosis
  • Caspase activation
  • Cryo-EM structure
  • Dark
  • Dronc
  • Programmed cell death

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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