Autoactivation of Procaspase-9 by Apaf-1-Mediated Oligomerization

We show that deletion of the Apaf-1 WD-40 repeats makes Apaf-1 constitutively active and capable of processing procaspase-9 independent of cytochrome c and dATP

Srinivasa M. Srinivasula; Manzoor Ahmad; Teresa Fernandes-Alnemri; Emad S. Alnemri

2004

Scholarcy highlights

  • Caspases are a family of cysteine proteases that cleave their substrates after aspartate residues and play key roles in apoptosis and inflammation
  • We show that deletion of the Apaf-1 WD-40 repeats makes Apaf-1 constitutively active and capable of processing procaspase-9 independent of cytochrome c and dATP
  • Apaf-1-mediated processing of procaspase-9 occurs at Asp-315 by an intrinsic autocatalytic activity of procaspase-9 itself
  • The procaspase is composed of three distinct functional modules: a prodomain and two catalytic subunits known as the large and small subunits
  • We provide evidence that processing of procaspase-9 occurs by an intrinsic autocatalytic activity of procaspase-9 itself, and that Apaf-1 triggers this activity by oligomerizing procaspase-9
  • We have demonstrated that removal of the WD-40 repeats makes Apaf-1 constitutively active, and capable of promoting procaspase-9 processing independent of cytochrome c and dATP
  • Both Bcl-xL and caspase-9–DN, which interact with Apaf-1, inhibit TRAIL-induced apoptosis, suggesting that the initial signal originating from the death receptors is amplified by activation of the Apaf-1 complex

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