5jul

Structural highlights

Function

APAF_DROME Main component of the apoptosome, an adapter protein complex that mediates activation of the caspase cascade in programmed cell death initiated by the intrinsic apoptosis pathway (PubMed:10984473, PubMed:16310803, PubMed:21220123, PubMed:25644603, PubMed:27916517). Recruits the initiator caspase Dronc, promoting its autocatalytic cleavage and activation; triggers the caspase cascade upstream of the effector caspases Drice and dcp-1 (PubMed:10619022, PubMed:10619023, PubMed:10984473, PubMed:21220123, PubMed:25644603). Effector of reaper, grim and hid induced cell killing (PubMed:10559939, PubMed:10619023, PubMed:16645639). Produces at least two isoforms that may activate distinct caspases by separate pathways (PubMed:10619023). Nucleotide binding protein with strong specificity for dATP; dATP binding is not essential, but promotes homooligomerization to form the apoptosome complex (PubMed:10619022, PubMed:10619023, PubMed:16310803, PubMed:21220123, PubMed:25644603, PubMed:27916517). There is currently no evidence of dATPase activity and structural analysis of the nucleotide binding pocket suggests negligible to no dATPase activity (Probable). Caspase activation by the apoptosome was initially thought to be dependent on binding of cytochrome c released from mitochondria, as is the case for vertebrate orthologs (PubMed:10619022, PubMed:10619023). Apoptosis induction by the Dark apoptosome appears to be cytochrome c independent (PubMed:11901172). Required for stress-induced apoptosis, for example in response to radiation (UV or gamma) or treatment with macromolecular synthesis inhibitors like cycloheximide and actinomycin D (PubMed:11901172, PubMed:16533943). Required for most, but not all programmed cell death during embryonic development (PubMed:16645639). Involved in developmental cell number regulation by apoptosis, particularly during neuronal and sensory organ development (PubMed:10559939, PubMed:10619022, PubMed:10619023, PubMed:16533943, PubMed:16645639). Involved in reduction of midline glial cell numbers by programmed cell death during embryogenesis (PubMed:16645639). During metamorphosis involved in removal of larval salivary glands by programmed cell death, but not of the larval midgut (PubMed:16533943).^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]}

References

1. ↑ Rodriguez A, Oliver H, Zou H, Chen P, Wang X, Abrams JM. Dark is a Drosophila homologue of Apaf-1/CED-4 and functions in an evolutionarily conserved death pathway. Nat Cell Biol. 1999 Sep;1(5):272-9. PMID:10559939 doi:10.1038/12984
2. ↑ Zhou L, Song Z, Tittel J, Steller H. HAC-1, a Drosophila homolog of APAF-1 and CED-4 functions in developmental and radiation-induced apoptosis. Mol Cell. 1999 Nov;4(5):745-55. PMID:10619022 doi:10.1016/s1097-2765(00)80385-8
3. ↑ Kanuka H, Sawamoto K, Inohara N, Matsuno K, Okano H, Miura M. Control of the cell death pathway by Dapaf-1, a Drosophila Apaf-1/CED-4-related caspase activator. Mol Cell. 1999 Nov;4(5):757-69. PMID:10619023 doi:10.1016/s1097-2765(00)80386-x
4. ↑ 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
5. ↑ Zimmermann KC, Ricci JE, Droin NM, Green DR. The role of ARK in stress-induced apoptosis in Drosophila cells. J Cell Biol. 2002 Mar 18;156(6):1077-87. PMID:11901172 doi:10.1083/jcb.20112068
6. ↑ Yu X, Wang L, Acehan D, Wang X, Akey CW. Three-dimensional structure of a double apoptosome formed by the Drosophila Apaf-1 related killer. J Mol Biol. 2006 Jan 20;355(3):577-89. PMID:16310803 doi:10.1016/j.jmb.2005.10.040
7. ↑ Mills K, Daish T, Harvey KF, Pfleger CM, Hariharan IK, Kumar S. The Drosophila melanogaster Apaf-1 homologue ARK is required for most, but not all, programmed cell death. J Cell Biol. 2006 Mar 13;172(6):809-15. PMID:16533943 doi:10.1083/jcb.200512126
8. ↑ Srivastava M, Scherr H, Lackey M, Xu D, Chen Z, Lu J, Bergmann A. ARK, the Apaf-1 related killer in Drosophila, requires diverse domains for its apoptotic activity. Cell Death Differ. 2007 Jan;14(1):92-102. PMID:16645639 doi:10.1038/sj.cdd.4401931
9. ↑ Yuan S, Yu X, Topf M, Dorstyn L, Kumar S, Ludtke SJ, Akey CW. Structure of the Drosophila apoptosome at 6.9 a resolution. Structure. 2011 Jan 12;19(1):128-40. PMID:21220123 doi:10.1016/j.str.2010.10.009
10. ↑ 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
11. ↑ Cheng TC, Akey IV, Yuan S, Yu Z, Ludtke SJ, Akey CW. A Near-Atomic Structure of the Dark Apoptosome Provides Insight into Assembly and Activation. Structure. 2017 Jan 3;25(1):40-52. doi: 10.1016/j.str.2016.11.002. Epub 2016 Dec , 1. PMID:27916517 doi:http://dx.doi.org/10.1016/j.str.2016.11.002
12. ↑ Cheng TC, Akey IV, Yuan S, Yu Z, Ludtke SJ, Akey CW. A Near-Atomic Structure of the Dark Apoptosome Provides Insight into Assembly and Activation. Structure. 2017 Jan 3;25(1):40-52. doi: 10.1016/j.str.2016.11.002. Epub 2016 Dec , 1. PMID:27916517 doi:http://dx.doi.org/10.1016/j.str.2016.11.002
13. ↑ Cheng TC, Akey IV, Yuan S, Yu Z, Ludtke SJ, Akey CW. A Near-Atomic Structure of the Dark Apoptosome Provides Insight into Assembly and Activation. Structure. 2017 Jan 3;25(1):40-52. doi: 10.1016/j.str.2016.11.002. Epub 2016 Dec , 1. PMID:27916517 doi:http://dx.doi.org/10.1016/j.str.2016.11.002