摘要：

Many steps in programmed cell death are evolutionarily conserved across different species. The Caenorhabditis elegans proteins CED‐9, CED‐4 and EGL‐1 involved in apoptosis are respectively homologous to anti‐apoptotic Bcl‐2 proteins, Apaf‐1 and the "BH3‐only" pro‐apototic proteins in mammals. In the linear apoptotic pathway of C. elegans, EGL‐1 binding to CED‐9 leads to the release of CED‐4 from CED‐9/CED‐4 complex. The molecular events leading to this process are not clearly elucidated. While the structures of CED‐9 apo, CED‐9/EGL‐1 and CED‐9/CED‐4 complexes are known, the CED‐9/CED‐4/EGL‐1 ternary complex structure is not yet determined. In this work, we modeled this ternary complex and performed molecular dynamics simulations of six different systems involving CED‐9. CED‐9 displays differential dynamics depending upon whether it is bound to CED‐4 and/or EGL‐1. CED‐4 exists as an asymmetric dimer (CED4a and CED4b) in CED‐9/CED‐4 complex. CED‐4a exhibits higher conformational flexibility when simulated without CED‐4b. Principal Component Analysis revealed that the direction of CED‐4a's winged‐helix domain motion differs in the ternary complex. Upon EGL‐1 binding, majority of non‐covalent interactions involving CARD domain in the CED‐4a‐CED‐9 interface have weakened and only half of the contacts found in the crystal structure between α/β domain of CED4a and CED‐9 are found to be stable. Additional stable contacts in the ternary complex and differential dynamics indicate that winged‐helix domain may play a key role in CED‐4a's dissociation from CED‐9. This study has provided a molecular level understanding of potential intermediate states that are likely to occur when CED‐4a is released from CED‐9.

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