Structure and activation mechanism of the Drosophila initiator caspase Dronc

Nieng Yan, Jun R. Huh, Virgil Schirf, Borries Demeler, Bruce A. Hay, Yigong Shi

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Abstract

Activation of an initiator caspase is essential to the execution of apoptosis. The molecular mechanisms by which initiator caspases are activated remain poorly understood. Here we demonstrate that the autocatalytic cleavage of Dronc, an important initiator caspase in Drosophila, results in a drastic enhancement of its catalytic activity in vitro. The autocleaved Dron forms a homodimer, whereas the uncleaved Dronc zymogen exists exclusively as a monomer. Thus the autocatalytic cleavage in Dronc induces its stable dimerization, which presumably allows the two adjacent monomers to mutually stabilize their active sites, leading to activation. Crystal structure of a prodomain-deleted Dronc zymogen, determined at 2.5 Å resolution, reveals an unproductive conformation at the active site, which is consistent with the observation that the zymogen remains catalytically inactive. This study revealed insights into mechanism of Dron activation, and in conjunction with other observations, suggests diverse mechanisms for the activation of initiator caspases.

Original languageEnglish (US)
Pages (from-to)8667-8674
Number of pages8
JournalJournal of Biological Chemistry
Volume281
Issue number13
DOIs
Publication statusPublished - Mar 31 2006

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Yan, N., Huh, J. R., Schirf, V., Demeler, B., Hay, B. A., & Shi, Y. (2006). Structure and activation mechanism of the Drosophila initiator caspase Dronc. Journal of Biological Chemistry, 281(13), 8667-8674. https://doi.org/10.1074/jbc.M513232200