A near atomic structure of the active human apoptosome.
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.
['Cheng|Tat Cheung|TC|', 'Hong|Chuan|C|', 'Akey|Ildikó V|IV|', 'Yuan|Shujun|S|', 'Akey|Christopher W|CW|0000-0002-3059-3121']
D053478:Apoptosomes D053477:Apoptotic Protease-Activating Factor 1 D053453:Caspase 9 D020285:Cryoelectron Microscopy D006801:Humans
human apoptosome procaspase-9 programmed cell death biophysics cell biology structural biology