title: A near atomic structure of the active human apoptosome.
abstract: 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.
authors.affiliation: Department of Physiology and Biophysics, Boston University School of Medicine, Boston, United States.
authors.forename: Tat Cheung
authors.initials: TC
authors.lastname: Cheng
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States.
authors.forename: Chuan
authors.initials: C
authors.lastname: Hong
authors.affiliation: Department of Physiology and Biophysics, Boston University School of Medicine, Boston, United States.
authors.forename: Ildikó V
authors.initials: IV
authors.lastname: Akey
authors.affiliation: Department of Biologics Research - Protein Sciences, U.S. Innovation Center, Bayer Healthcare, San Franciso, United States.
authors.forename: Shujun
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Department of Physiology and Biophysics, Boston University School of Medicine, Boston, United States.
authors.forename: Christopher W
authors.identifier: 0000-0002-3059-3121
authors.initials: CW
authors.lastname: Akey
mesh_terms: D053478:Apoptosomes / Q000737:chemistry* / Q000648:ultrastructure*; D053477:Apoptotic Protease-Activating Factor 1 / Q000032:analysis*; D053453:Caspase 9 / Q000032:analysis*; D020285:Cryoelectron Microscopy; D006801:Humans
chemical_list: C506592:APAF1 protein, human; D053478:Apoptosomes; D053477:Apoptotic Protease-Activating Factor 1; D053453:Caspase 9
keywords: apoptosome; biophysics; cell biology; human; procaspase-9; programmed cell death; structural biology