Caspase-9, Bcl-XL, and Apaf-1 Form a Ternary Complex*
Abstract
Genetic analysis of apoptosis in the nematodeCaenorhabditis elegans has revealed the cell death machine to be composed of three core interacting components. CED-4 (equivalent to mammalian Apaf-1) is a nucleotide binding molecule that complexes with the zymogen form of the death protease CED-3, leading to its autoactivation and cell death. CED-9 blocks death by complexing with CED-4 and attenuating its ability to promote CED-3 activation. An equivalent ternary complex was found to be present in mammalian cells involving Apaf-1, the mammalian death protease caspase-9, and Bcl-XL, an anti-apoptotic member of the Bcl-2 family. Consistent with a central role for caspase-9, a dominant negative form effectively inhibited cell death initiated by a wide variety of inducers.
Footnotes
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↵* This work was supported by National Institutes of Health Grants ES08111 and DAMD 17-96-6085.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‡ Holds a Special Fellowship from the Leukemia Society of America.
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↵§ Present address: Genentech, Inc., 1 DNA Way, M/S-40, South San Francisco, CA 94080.
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↵¶ To whom correspondence should be addressed. Present address: Genentech, Inc., 1 DNA Way, M/S-40, South San Francisco, CA 94080. Tel.: 650-225-1312; Fax: 650-225-6443; E-mail: dixit{at}gene.com.
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↵1 The abbreviations used are: FADD, Fas-associated death domain; RAIDD, RIP-associated ICH-1/CED-3-homologous protein with a death domain; TRADD, tumor necrosis factor-associated death domain. TNF, tumor necrosis factor; mAb, monoclonal antibody.
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- Received November 18, 1997.
- Revision received December 24, 1997.
- The American Society for Biochemistry and Molecular Biology, Inc.
