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Molecular mechanisms of DrICE inhibition by DIAP1 and removal of inhibition by Reaper, Hid and Grim

Nature Structural & Molecular Biology volume 11, pages 420–428 (2004)Cite this article

Abstract

The Drosophila melanogaster inhibitor of apoptosis protein DIAP1 suppresses apoptosis in part through inhibition of the effector caspase DrICE. The pro-death proteins Reaper, Hid and Grim (RHG) induce apoptosis by antagonizing DIAP1 function. However, the underlying molecular mechanisms remain unknown. Here we demonstrate that DIAP1 directly inhibits the catalytic activity of DrICE through its BIR1 domain and this inhibition is countered effectively by the RHG proteins. Inhibition of DrICE by DIAP1 occurs only after the cleavage of its N-terminal 20 amino acids and involves a conserved surface groove on BIR1. Crystal structures of BIR1 bound to the RHG peptides show that the RHG proteins use their N-terminal IAP-binding motifs to bind to the same surface groove, hence relieving DIAP1-mediated inhibition of DrICE. These studies define novel molecular mechanisms for the inhibition and activation of a representative D. melanogaster effector caspase.

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Figure 1: The BIR1 domain of DIAP1 is necessary and sufficient for the inhibition of the catalytic activity of DrICE.
Figure 2: The conserved pocket of DIAP1-BIR1 is involved in DrICE interaction and inhibition.
Figure 3: The N-terminal residues of Hid antagonize DIAP1 function by displacing DIAP1 from DrICE.
Figure 4: A mechanistic explanation for developmental GOF mutations in the BIR1 domain.
Figure 5: Structural basis of recognition of the RHG peptides by DIAP1-BIR1.
Figure 6: The autoinhibition of DIAP1 resides in its N-terminal 20 residues.

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Acknowledgements

We thank L. Walsh at CHESS for help with beam time and T.K. Vanderlick and M. Apel-Paz for help with ITC. This work was supported by US National Institutes of Health grants.

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Authors and Affiliations

  1. Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, Washington Road, Princeton, 08544, New Jersey, USA

    Nieng Yan, Jijie Chai, Wenyu Li & Yigong Shi

  2. Department of Biology, Tsinghua University, Beijing, 100084, China

    Jia-Wei Wu

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Correspondence to Yigong Shi.

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Yan, N., Wu, JW., Chai, J. et al. Molecular mechanisms of DrICE inhibition by DIAP1 and removal of inhibition by Reaper, Hid and Grim. Nat Struct Mol Biol 11, 420–428 (2004). https://doi.org/10.1038/nsmb764

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