Abstract
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.
Keywords
Cytochrome cActivator (genetics)CaspaseCell biologyProteaseApoptosisLinkerCytochromeBiologyChemistryProgrammed cell deathBiochemistryMitochondrionMolecular biologyEnzymeGene
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Publication Info
- Year
- 1999
- Type
- article
- Volume
- 274
- Issue
- 30
- Pages
- 20855-20860
- Citations
- 115
- Access
- Closed
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Cite This
Colin Adrain,
Elizabeth A. Slee,
Mary T. Harte
et al.
(1999).
Regulation of Apoptotic Protease Activating Factor-1 Oligomerization and Apoptosis by the WD-40 Repeat Region.
Journal of Biological Chemistry
, 274
(30)
, 20855-20860.
https://doi.org/10.1074/jbc.274.30.20855
Identifiers
- DOI
- 10.1074/jbc.274.30.20855