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Structure of the CED-4–CED-9 complex provides insights into programmed cell death in Caenorhabditis elegans

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  • Nieng Yan

    (Princeton University, Lewis Thomas Laboratory)

  • Jijie Chai

    (Princeton University, Lewis Thomas Laboratory)

  • Eui Seung Lee

    (University of Colorado
    Gwangju Institute of Science and Technology)

  • Lichuan Gu

    (Princeton University, Lewis Thomas Laboratory)

  • Qun Liu

    (Cornell University)

  • Jiaqing He

    (Brookhaven National Laboratory)

  • Jia-Wei Wu

    (Princeton University, Lewis Thomas Laboratory)

  • David Kokel

    (University of Colorado)

  • Huilin Li

    (Brookhaven National Laboratory)

  • Quan Hao

    (Cornell University)

  • Ding Xue

    (University of Colorado)

  • Yigong Shi

    (Princeton University, Lewis Thomas Laboratory)

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 Å 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.

Suggested Citation

  • Nieng Yan & Jijie Chai & Eui Seung Lee & Lichuan Gu & Qun Liu & Jiaqing He & Jia-Wei Wu & David Kokel & Huilin Li & Quan Hao & Ding Xue & Yigong Shi, 2005. "Structure of the CED-4–CED-9 complex provides insights into programmed cell death in Caenorhabditis elegans," Nature, Nature, vol. 437(7060), pages 831-837, October.
    • Handle: RePEc:nat:nature:v:437:y:2005:i:7060:d:10.1038_nature04002
    DOI: 10.1038/nature04002
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    Cited by:

    1. Yuang Wu & Yue Sun & Evelyne Richet & Zhifu Han & Jijie Chai, 2023. "Structural basis for negative regulation of the Escherichia coli maltose system," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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