The apoptosome: a cell death signaling platform

In the intrinsic death pathway, cytochrome c binds to Apaf-1 and triggers apoptosome assembly in the presence of dATP. This platform binds procaspase-9, which activates procaspase-3 and other downstream procaspases. To understand this process, we determined a structure of the active pc-9 human apoptosome at near atomic resolution and created a model of this heptameric platform, which contains 49 domains, 7 cytochrome c molecules and 3-4 well ordered pc-9 CARDs. Further studies of the active apoptosome should provide additional insights into the assembly and function of this cell killer, which has a complicated and still mysterious activation program. In parallel studies, we determined a near atomic structure of the Drosophila Apaf-1 related killer (Dark) in the ground state. A comparison of human and Drosophila apoptosome structures provides a possible explanation for their nucleotide preferences.

Click on figure for apoptosome movie

3D map depicts cell ‘wheel of death’ in action – Futurity

Dorstyn L., Akey C.W., and Kumar S. (2018). New insights into apoptosome structure and function. Cell Death Differ. 2018 Jul;25(7):1194-1208. doi: 10.1038/s41418-017-0025-z. Review. PMID: 29765111

Cheng, T.C., Akey, I.V., Yuan, S., Yu, Z., Ludtke, S.J. and Akey, C.W. (2017). A near atomic structure of the Dark apoptosome provides insight into assembly and activation. Structure 25:40-52. doi:10.1016/j.str.2016.11.002. PMID: 27916517

Cheng, T.C., Hong, C., Akey, I.V., Yuan, S. and Akey, C.W. (2016). A near atomic structure of the active human apoptosome. Elife. Oct 4;5. pii: e17755. doi: 10.7554/eLife.17755. PMID: 27697150