title: Structural Insights into DD-Fold Assembly and Caspase-9 Activation by the Apaf-1 Apoptosome.
abstract: Death domain (DD)-fold assemblies play a crucial role in regulating the signaling to cell survival or death. Here we report the crystal structure of the caspase recruitment domain (CARD)-CARD disk of the human apoptosome. The structure surprisingly reveals that three 1:1 Apaf-1:procaspase-9 CARD protomers form a novel helical DD-fold assembly on the heptameric wheel-like platform of the apoptosome. The small-angle X-ray scattering and multi-angle light scattering data also support that three protomers could form an oligomeric complex similar to the crystal structure. Interestingly, the quasi-equivalent environment of CARDs could generate different quaternary CARD assemblies. We also found that the type II interaction is conserved in all DD-fold complexes, whereas the type I interaction is found only in the helical DD-fold assemblies. This study provides crucial insights into the caspase activation mechanism, which is tightly controlled by a sophisticated and highly evolved CARD assembly on the apoptosome, and also enables better understanding of the intricate DD-fold assembly.
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan; Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Academia, Sinica, Taipei 11529, Taiwan; Institute of Biochemical Sciences, National Taiwan University, Taipei 10617, Taiwan.
authors.forename: Tsung-Wei
authors.initials: TW
authors.lastname: Su
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Chao-Yu
authors.initials: CY
authors.lastname: Yang
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Wen-Pin
authors.initials: WP
authors.lastname: Kao
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 70101, Taiwan.
authors.forename: Bai-Jiun
authors.initials: BJ
authors.lastname: Kuo
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 70101, Taiwan.
authors.forename: Shan-Meng
authors.initials: SM
authors.lastname: Lin
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan.
authors.forename: Jung-Yaw
authors.initials: JY
authors.lastname: Lin
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 70101, Taiwan; Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 70101, Taiwan; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan 70101, Taiwan. Electronic address: gracelo@mail.ncku.edu.tw.
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Lo
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan; Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Academia, Sinica, Taipei 11529, Taiwan. Electronic address: tomlin@gate.sinica.edu.tw.
authors.forename: Su-Chang
authors.initials: SC
authors.lastname: Lin
mesh_terms: D017209:Apoptosis; D053478:Apoptosomes / Q000737:chemistry* / Q000378:metabolism; D053477:Apoptotic Protease-Activating Factor 1 / Q000737:chemistry / Q000378:metabolism*; D053453:Caspase 9 / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D000072417:Protein Domains; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D053838:Scattering, Small Angle
chemical_list: C506592:APAF1 protein, human; D053478:Apoptosomes; D053477:Apoptotic Protease-Activating Factor 1; C506433:CASP9 protein, human; D053453:Caspase 9
keywords: CARD; CED-4; DARK; DED; SAXS; apoptosis; caspase activation; crystal structure; helical assembly; protomer