Regulation of apoptotic protease activating factor-1 oligomerization and apoptosis by the WD-40 repeat region

C Adrain, E A Slee, M T Harte, S J Martin

Research output: Contribution to journalArticlepeer-review

98 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)20855-60
Number of pages6
JournalJournal of Biological Chemistry
Volume274
Issue number30
Publication statusPublished - 23 Jul 1999

Keywords

  • Apoptosis
  • Apoptotic Protease-Activating Factor 1
  • Binding Sites
  • Caspase 9
  • Caspases
  • Cell Line
  • Dimerization
  • Enzyme Activation
  • Humans
  • Proteins
  • Repetitive Sequences, Nucleic Acid
  • Saccharomyces cerevisiae

Fingerprint Dive into the research topics of 'Regulation of apoptotic protease activating factor-1 oligomerization and apoptosis by the WD-40 repeat region'. Together they form a unique fingerprint.

Cite this