5WVE

Apaf-1-Caspase-9 holoenzyme

Summary for 5WVE

• Entry DOI: 10.2210/pdb5wve/pdb
• EMDB information: 6690
• Descriptor: Apoptotic protease-activating factor 1, Cytochrome c, Caspase, ... (7 entities in total)
• Functional Keywords: apoptosis holoenzyme, apoptosis
• Biological source: Homo sapiens (Human); More
• Cellular location: Cytoplasm : O14727 O14727; Mitochondrion intermembrane space: P00004
• Total number of polymer chains: 25
• Total formula weight: 1213030.43

Authors

Li, Y.,Zhou, M.,Hu, Q.,Shi, Y. (deposition date: 2016-12-24, release date: 2017-02-08, Last modification date: 2024-11-13)

Primary citation

Li, Y.,Zhou, M.,Hu, Q.,Bai, X.-C.,Huang, W.,Scheres, S.H.W.,Shi, Y.
Mechanistic insights into caspase-9 activation by the structure of the apoptosome holoenzyme
Proc. Natl. Acad. Sci. U.S.A., 114:1542-1547, 2017

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 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.

PubMed: 28143931
DOI: 10.1073/pnas.1620626114

Experimental method

ELECTRON MICROSCOPY (4.4 Å)