A near atomic structure of the active human apoptosome

• Main Authors: Tat Cheung Cheng, Chuan Hong, Ildikó V Akey, Shujun Yuan, Christopher W Akey
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2016-10-01
• Series: eLife
• Subjects: apoptosome; programmed cell death; procaspase-9
• Online Access: https://elifesciences.org/articles/17755

In response to cell death signals, an active apoptosome is assembled from Apaf-1 and procaspase-9 (pc-9). Here we report a near atomic structure of the active human apoptosome determined by cryo-electron microscopy. The resulting model gives insights into cytochrome c binding, nucleotide exchange and conformational changes that drive assembly. During activation an acentric disk is formed on the central hub of the apoptosome. This disk contains four Apaf-1/pc-9 CARD pairs arranged in a shallow spiral with the fourth pc-9 CARD at lower occupancy. On average, Apaf-1 CARDs recruit 3 to 5 pc-9 molecules to the apoptosome and one catalytic domain may be parked on the hub, when an odd number of zymogens are bound. This suggests a stoichiometry of one or at most, two pc-9 dimers per active apoptosome. Thus, our structure provides a molecular framework to understand the role of the apoptosome in programmed cell death and disease.