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Structure and Activation Mechanism of the Drosophila Initiator Caspase Dronc

Yan, Nieng and Huh, Jun R. and Schirf, Virgil and Demeler, Borries and Hay, Bruce A. and Shi, Yigong (2006) Structure and Activation Mechanism of the Drosophila Initiator Caspase Dronc. Journal of Biological Chemistry, 281 (13). pp. 8667-8674. ISSN 0021-9258. doi:10.1074/jbc.M513232200. https://resolver.caltech.edu/CaltechAUTHORS:YANjbc06

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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 Dronc 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 Dronc activation, and in conjunction with other observations, suggests diverse mechanisms for the activation of initiator caspases.


Item Type:Article
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https://dx.doi.org/10.1074/jbc.M513232200DOIArticle
Additional Information:© 2006 the American Society for Biochemistry and Molecular Biology. Received for publication, December 12, 2005 , and in revised form, January 17, 2006. We thank Lana Walsh for beam time at CHESS and Michael Becker for beam time at Brookhaven National Laboratory. The development of the UltraScan Software is supported by the National Science Foundation through Grant DBI-9974819 to B. Demeler. The atomic coordinates and structure factors (code 2FP3) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/). This work was supported by grants from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. The on-line version of this article (available at http://www.jbc.org) contains supplemental text on analytical ultracentrifugation and four supplemental figures.
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Funding AgencyGrant Number
NSFDBI-9974819
NIHUNSPECIFIED
Issue or Number:13
DOI:10.1074/jbc.M513232200
Record Number:CaltechAUTHORS:YANjbc06
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:YANjbc06
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:4717
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:05 Sep 2006
Last Modified:08 Nov 2021 20:19

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