| Structural highlights
Function
[ICENC_DROME] Involved in the activation cascade of caspases responsible for apoptosis execution. Effector of steroid-mediated apoptosis during insect metamorphosis. Overexpression promotes programmed cell death. Interaction with th is required to suppress Nc-mediated cell death; via th-mediated ubiquitination of Nc. Rate-limiting caspase in rpr and W death pathway.[1] [2] [3] [4]
Publication Abstract from PubMed
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 A 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 A 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.
Structure of the apoptosome: mechanistic insights into activation of an initiator caspase from Drosophila.,Pang Y, Bai XC, Yan C, Hao Q, Chen Z, Wang JW, Scheres SH, Shi Y Genes Dev. 2015 Feb 1;29(3):277-87. doi: 10.1101/gad.255877.114. PMID:25644603[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Dorstyn L, Colussi PA, Quinn LM, Richardson H, Kumar S. DRONC, an ecdysone-inducible Drosophila caspase. Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4307-12. PMID:10200258
- ↑ Meier P, Silke J, Leevers SJ, Evan GI. The Drosophila caspase DRONC is regulated by DIAP1. EMBO J. 2000 Feb 15;19(4):598-611. PMID:10675329 doi:http://dx.doi.org/10.1093/emboj/19.4.598
- ↑ Quinn LM, Dorstyn L, Mills K, Colussi PA, Chen P, Coombe M, Abrams J, Kumar S, Richardson H. An essential role for the caspase dronc in developmentally programmed cell death in Drosophila. J Biol Chem. 2000 Dec 22;275(51):40416-24. PMID:10984473 doi:http://dx.doi.org/10.1074/jbc.M002935200
- ↑ Chai J, Yan N, Huh JR, Wu JW, Li W, Hay BA, Shi Y. Molecular mechanism of Reaper-Grim-Hid-mediated suppression of DIAP1-dependent Dronc ubiquitination. Nat Struct Biol. 2003 Nov;10(11):892-8. Epub 2003 Sep 28. PMID:14517550 doi:10.1038/nsb989
- ↑ Pang Y, Bai XC, Yan C, Hao Q, Chen Z, Wang JW, Scheres SH, Shi Y. Structure of the apoptosome: mechanistic insights into activation of an initiator caspase from Drosophila. Genes Dev. 2015 Feb 1;29(3):277-87. doi: 10.1101/gad.255877.114. PMID:25644603 doi:http://dx.doi.org/10.1101/gad.255877.114
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