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Mechanistic insights into CED-4-mediated activation of CED-3
Weijiao Huang1，2， Tianyu Jiang1，2， Wooyoung Choi1，2， Shiqian Qi1，2， Yuxuan Pang1，2， Qi Hu1，2， Yanhui Xu3， Xinqi Gong1，2， Philip D. Jeffrey4， Jiawei Wang5 and Yigong Shi1，2，6
Programmed cell death in Caenorhabditis elegans requires activation of the caspase CED-3， which strictly depends on CED-4. CED-4 forms an octameric apoptosome， which binds the CED-3 zymogen and facilitates its autocatalytic maturation. Despite recent advances， major questions remain unanswered. Importantly， how CED-4 recognizes CED-3 and how such binding facilitates CED-3 activation remain completely unknown. Here we demonstrate that the L2′ loop of CED-3 directly binds CED-4 and plays a major role in the formation of an active CED-4–CED-3 holoenzyme. The crystal structure of the CED-4 apoptosome bound to the L2′ loop fragment of CED-3， determined at 3.2 ？ resolution， reveals specific interactions between a stretch of five hydrophobic amino acids from CED-3 and a shallow surface pocket within the hutch of the funnel-shaped CED-4 apoptosome. Structure-guided biochemical analysis confirms the functional importance of the observed CED-4–CED-3 interface. Structural analysis together with published evidence strongly suggest a working model in which two molecules of CED-3 zymogen， through specific recognition， are forced into the hutch of the CED-4 apoptosome， consequently undergoing dimerization and autocatalytic maturation. The mechanism of CED-3 activation represents a major revision of the prevailing model for initiator caspase activation.
