RT Journal Article
SR Electronic
T1 Structural insights into CED-3 activation
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202302056
DO 10.26508/lsa.202302056
VO 6
IS 9
A1 Li, Yini
A1 Tian, Lu
A1 Zhang, Ying
A1 Shi, Yigong
YR 2023
UL http://www.life-science-alliance.org/content/6/9/e202302056.abstract
AB In Caenorhabditis elegans (C. elegans), onset of programmed cell death is marked with the activation of CED-3, a process that requires assembly of the CED-4 apoptosome. Activated CED-3 forms a holoenzyme with the CED-4 apoptosome to cleave a wide range of substrates, leading to irreversible cell death. Despite decades of investigations, the underlying mechanism of CED-4–facilitated CED-3 activation remains elusive. Here, we report cryo-EM structures of the CED-4 apoptosome and three distinct CED-4/CED-3 complexes that mimic different activation stages for CED-3. In addition to the previously reported octamer in crystal structures, CED-4, alone or in complex with CED-3, exists in multiple oligomeric states. Supported by biochemical analyses, we show that the conserved CARD–CARD interaction promotes CED-3 activation, and initiation of programmed cell death is regulated by the dynamic organization of the CED-4 apoptosome.