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Structural and biochemical basis of apoptotic activation by Smac/DIABLO

Author

Listed:
  • Jijie Chai

    (Department of Molecular Biology Princeton University)

  • Chunying Du

    (University of Texas Southwestern Medical Center)

  • Jia-Wei Wu

    (Department of Molecular Biology Princeton University)

  • Saw Kyin

    (Department of Molecular Biology Princeton University)

  • Xiaodong Wang

    (University of Texas Southwestern Medical Center)

  • Yigong Shi

    (Department of Molecular Biology Princeton University)

Abstract

Apoptosis (programmed cell death), an essential process in the development and homeostasis of metazoans, is carried out by caspases. The mitochondrial protein Smac/DIABLO performs a critical function in apoptosis by eliminating the inhibitory effect of IAPs (inhibitor of apoptosis proteins) on caspases. Here we show that Smac/DIABLO promotes not only the proteolytic activation of procaspase-3 but also the enzymatic activity of mature caspase-3, both of which depend upon its ability to interact physically with IAPs. The crystal structure of Smac/DIABLO at 2.2 Å resolution reveals that it homodimerizes through an extensive hydrophobic interface. Missense mutations inactivating this dimeric interface significantly compromise the function of Smac/DIABLO. As in the Drosophila proteins Reaper, Grim and Hid, the amino-terminal amino acids of Smac/DIABLO are indispensable for its function, and a seven-residue peptide derived from the amino terminus promotes procaspase-3 activation in vitro. These results establish an evolutionarily conserved structural and biochemical basis for the activation of apoptosis by Smac/DIABLO.

Suggested Citation

  • Jijie Chai & Chunying Du & Jia-Wei Wu & Saw Kyin & Xiaodong Wang & Yigong Shi, 2000. "Structural and biochemical basis of apoptotic activation by Smac/DIABLO," Nature, Nature, vol. 406(6798), pages 855-862, August.
    • Handle: RePEc:nat:nature:v:406:y:2000:i:6798:d:10.1038_35022514
    DOI: 10.1038/35022514
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    Cited by:

    1. Shuo-Shuo Liu & Tian-Xia Jiang & Fan Bu & Ji-Lan Zhao & Guang-Fei Wang & Guo-Heng Yang & Jie-Yan Kong & Yun-Fan Qie & Pei Wen & Li-Bin Fan & Ning-Ning Li & Ning Gao & Xiao-Bo Qiu, 2024. "Molecular mechanisms underlying the BIRC6-mediated regulation of apoptosis and autophagy," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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