Structural Insights into DD-Fold Assembly and Caspase-9 Activation by the Apaf-1 Apoptosome

Tsung-Wei Su; Chao-Yu Yang; Wen-Pin Kao; Bai-Jiun Kuo; Shan-Meng Lin; Jung-Yaw Lin; Yu-Chih Lo; Su-Chang Lin

doi:10.1016/j.str.2016.12.019

Structural Insights into DD-Fold Assembly and Caspase-9 Activation by the Apaf-1 Apoptosome

Structure. 2017 Mar 7;25(3):407-420. doi: 10.1016/j.str.2016.12.019. Epub 2017 Jan 19.

Authors

Tsung-Wei Su¹, Chao-Yu Yang², Wen-Pin Kao², Bai-Jiun Kuo³, Shan-Meng Lin³, Jung-Yaw Lin⁴, Yu-Chih Lo⁵, Su-Chang Lin⁶

Affiliations

¹ 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.
² Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan.
³ Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 70101, Taiwan.
⁴ Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan.
⁵ 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: [email protected].
⁶ 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: [email protected].

PMID: 28111022
DOI: 10.1016/j.str.2016.12.019

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.

Keywords: CARD; CED-4; DARK; DED; SAXS; apoptosis; caspase activation; crystal structure; helical assembly; protomer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis
Apoptosomes / chemistry*
Apoptosomes / metabolism
Apoptotic Protease-Activating Factor 1 / chemistry
Apoptotic Protease-Activating Factor 1 / metabolism*
Caspase 9 / chemistry
Caspase 9 / metabolism*
Crystallography, X-Ray
Enzyme Activation
Humans
Models, Molecular
Protein Binding
Protein Domains
Protein Multimerization
Protein Structure, Secondary
Scattering, Small Angle

Substances

APAF1 protein, human
Apoptosomes
Apoptotic Protease-Activating Factor 1
CASP9 protein, human
Caspase 9