Structural and biochemical basis of apoptotic activation by Smac/DIABLO

Jijie Chai, Chunying Du, Jia-Wei Wu, Saw Kyin, Xiaodong Wang and Yigong Shi ()
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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

Nature, 2000, vol. 406, issue 6798, 855-862

Abstract: 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.

Date: 2000
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DOI: 10.1038/35022514

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