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Updated: Jul 14, 2026
A High-throughput, High-content, Liquid-based C. elegans Pathosystem
Published on: July 1, 2018
Structure of the CED-4-CED-9 complex provides insights into programmed cell death in Caenorhabditis elegans
Nieng Yan1, Jijie Chai, Eui Seung Lee
1Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, Washington Road, Princeton, New Jersey 08544, USA.
Insights
The EGL-1 protein releases CED-4 from CED-9 inhibition, allowing CED-4 to activate CED-3 and initiate programmed cell death in C. elegans.
Area of Science:
- Molecular Biology
- Developmental Biology
- Genetics
Background:
- Programmed cell death (apoptosis) is crucial for development and tissue homeostasis.
- In Caenorhabditis elegans, the egl-1, ced-9, ced-4, and ced-3 genes regulate apoptosis.
- CED-4 activates the caspase CED-3, but is inhibited by CED-9 until EGL-1 intervenes.
Purpose of the Study:
- To elucidate the structural basis of CED-4 inhibition by CED-9.
- To reconstitute and analyze the CED-3 activation pathway.
- To understand the role of EGL-1 in releasing CED-4 inhibition.
Main Methods:
- X-ray crystallography to determine the CED-4-CED-9 complex structure at 2.6 Å resolution.
- Biochemical reconstitution of the CED-3 activation pathway using purified CED-4, CED-9, and EGL-1 proteins.
Main Results:
- The crystal structure revealed that one CED-9 molecule binds to an asymmetric CED-4 dimer, interacting specifically with one CED-4 subunit.
- This specific CED-9 binding inhibits CED-4's ability to activate CED-3.
- EGL-1 binding induced conformational changes in CED-9, leading to CED-4 dissociation, subsequent CED-4 dimerization into a tetramer, and autoactivation of CED-3.
Conclusions:
- The study provides a structural mechanism for CED-9-mediated inhibition of CED-4.
- EGL-1 acts as a trigger, inducing CED-9 conformational changes that release CED-4.
- The findings illuminate the regulatory cascade controlling programmed cell death initiation in C. elegans.
Abstract:
Interplay among four genes--egl-1, ced-9, ced-4 and ced-3--controls the onset of programmed cell death in the nematode Caenorhabditis elegans. Activation of the cell-killing protease CED-3 requires CED-4. However, CED-4 is constitutively inhibited by CED-9 until its release by EGL-1. Here we report the crystal structure of the CED-4-CED-9 complex at 2.6 A resolution, and a complete reconstitution of the CED-3 activation pathway using homogeneous proteins of CED-4, CED-9 and EGL-1. One molecule of CED-9 binds to an asymmetric dimer of CED-4, but specifically recognizes only one of the two CED-4 molecules. This specific interaction prevents CED-4 from activating CED-3. EGL-1 binding induces pronounced conformational changes in CED-9 that result in the dissociation of the CED-4 dimer from CED-9. The released CED-4 dimer further dimerizes to form a tetramer, which facilitates the autoactivation of CED-3. Together, our studies provide important insights into the regulation of cell death activation in C. elegans.
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