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J. Biol. Chem., Vol. 281, Issue 13, 8667-8674, March 31, 2006

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Structure and Activation Mechanism of the Drosophila Initiator Caspase Dronc^*

Nieng Yan, Jun R. Huh, Virgil Schirf^¶, Borries Demeler^¶, Bruce A. Hay, and Yigong Shi¹

From the Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, Princeton, New Jersey 08544, the Division of Biology, California Institute of Technology, Pasadena, California 91125, and the ^¶Department of Biochemistry, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900

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.

Received for publication, December 12, 2005 , and in revised form, January 17, 2006.

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.

¹ To whom correspondence should be addressed: Dept. of Molecular Biology, Princeton University, Lewis Thomas Laboratory, Washington Rd., Princeton, NJ 08544. Tel.: 609-258-6071; Fax: 609-258-6730; E-mail: ygshi{at}princeton.edu.

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