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J Biol Chem, Vol. 274, Issue 30, 20855-20860, July 23, 1999

Regulation of Apoptotic Protease Activating Factor-1 Oligomerization and Apoptosis by the WD-40 Repeat Region

Colin Adrain, Elizabeth A. Slee, Mary T. Harte, and Seamus J. Martin

From the Molecular Cell Biology Laboratory, Department of Biology, National University of Ireland, Maynooth, County Kildare, Ireland

Apoptotic protease activating factor-1 (Apaf-1) has been identified as a proximal activator of caspase-9 in cell death pathways that trigger mitochondrial damage and cytochrome c release. The mechanism of Apaf-1 action is unclear but has been proposed to involve the clustering of caspase-9 molecules, thereby facilitating autoprocessing of adjacent zymogens. Here we show that Apaf-1 can dimerize via the CED-4 homologous and linker domains of the molecule providing a means by which Apaf-1 can promote the clustering of caspase-9 and facilitate its activation. Apaf-1 dimerization was repressed by the C-terminal half of the molecule, which contains multiple WD-40 repeats, but this repression was overcome in the presence of cytochrome c and dATP. Removal of the WD-40 repeat region resulted in a constitutively active Apaf-1 that exhibited greater cytotoxicity in transient transfection assays when compared with full-length Apaf-1. These data suggest a mechanism for Apaf-1 function and reveal an important regulatory role for the WD-40 repeat region.

Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.


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