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Title | Mechanistic insights into caspase-9 activation by the structure of the apoptosome holoenzyme. |
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Journal, issue, pages | Proc Natl Acad Sci U S A, Vol. 114, Issue 7, Page 1542-1547, Year 2017 |
Publish date | Feb 14, 2017 |
Authors | Yini Li / Mengying Zhou / Qi Hu / Xiao-Chen Bai / Weiyun Huang / Sjors H W Scheres / Yigong Shi / |
PubMed Abstract | Mammalian intrinsic apoptosis requires activation of the initiator caspase-9, which then cleaves and activates the effector caspases to execute cell killing. The heptameric Apaf-1 apoptosome is ...Mammalian intrinsic apoptosis requires activation of the initiator caspase-9, which then cleaves and activates the effector caspases to execute cell killing. The heptameric Apaf-1 apoptosome is indispensable for caspase-9 activation by together forming a holoenzyme. The molecular mechanism of caspase-9 activation remains largely enigmatic. Here, we report the cryoelectron microscopy (cryo-EM) structure of an apoptotic holoenzyme and structure-guided biochemical analyses. The caspase recruitment domains (CARDs) of Apaf-1 and caspase-9 assemble in two different ways: a 4:4 complex docks onto the central hub of the apoptosome, and a 2:1 complex binds the periphery of the central hub. The interface between the CARD complex and the central hub is required for caspase-9 activation within the holoenzyme. Unexpectedly, the CARD of free caspase-9 strongly inhibits its proteolytic activity. These structural and biochemical findings demonstrate that the apoptosome activates caspase-9 at least in part through sequestration of the inhibitory CARD domain. |
External links | Proc Natl Acad Sci U S A / PubMed:28143931 / PubMed Central |
Methods | EM (single particle) |
Resolution | 4.4 - 6.9 Å |
Structure data | EMDB-6691: EMDB-6692: |
Chemicals | ChemComp-DTP: ChemComp-MG: ChemComp-HEM: |
Source |
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Keywords | APOPTOSIS / apoptosis holoenzyme |