Crystal structure of the Caenorhabditis elegans apoptosome reveals an octameric assembly of CED-4.
The CED-4 homo-oligomer or apoptosome is required for initiation of programmed cell death in Caenorhabditis elegans by facilitating autocatalytic activation of the CED-3 caspase zymogen. How the CED-4 apoptosome assembles and activates CED-3 remains enigmatic. Here we report the crystal structure of the complete CED-4 apoptosome and show that it consists of eight CED-4 molecules, organized as a tetramer of an asymmetric dimer via a previously unreported interface among AAA(+) ATPases. These eight CED-4 molecules form a funnel-shaped structure. The mature CED-3 protease is monomeric in solution and forms an active holoenzyme with the CED-4 apoptosome, within which the protease activity of CED-3 is markedly stimulated. Unexpectedly, the octameric CED-4 apoptosome appears to bind only two, not eight, molecules of mature CED-3. The structure of the CED-4 apoptosome reveals shared principles for the NB-ARC family of AAA(+) ATPases and suggests a mechanism for the activation of CED-3.
Qi
Shiqian
S
Ministry of Education Protein Science Laboratory, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
Pang
Yuxuan
Y
Hu
Qi
Q
Liu
Qun
Q
Li
Hua
H
Zhou
Yulian
Y
He
Tianxi
T
Liang
Qionglin
Q
Liu
Yexing
Y
Yuan
Xiaoqiu
X
Luo
Guoan
G
Li
Huilin
H
Wang
Jiawei
J
Yan
Nieng
N
Shi
Yigong
Y
D000595:Amino Acid Sequence; D000818:Animals; D053478:Apoptosomes / Q000378:metabolism; D053477:Apoptotic Protease-Activating Factor 1 / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000737:chemistry / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry*; D002135:Calcium-Binding Proteins / Q000737:chemistry*; D020169:Caspases / Q000737:chemistry; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D016415:Sequence Alignment; D014961:X-Ray Diffraction
D053478:Apoptosomes; D053477:Apoptotic Protease-Activating Factor 1; D029742:Caenorhabditis elegans Proteins; D002135:Calcium-Binding Proteins; C089224:Ced-4 protein, C elegans; D020169:Caspases; C089223:ced-3 protein, C elegans