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Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation
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The holo-apoptosome: activation of procaspase-9 and interactions with caspase-3

Shujun Yuan1, Xinchao Yu, John M Asara

  • 1Department of Physiology and Biophysics, Boston University School of Medicine, 700 Albany Street, Boston, MA 02118-2526, USA.

Structure (London, England : 1993)
|August 11, 2011
PubMed

Insights

The apoptosome

Area of Science:

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Background:

  • The intrinsic cell death pathway is crucial for cellular homeostasis.
  • Activation of procaspase-9 (PC-9) on the apoptosome is a key regulatory step.

Purpose of the Study:

  • To elucidate the structural organization of the apoptosome.
  • To understand the mechanism of procaspase-9 activation.
  • To investigate the interaction between procaspase-9 and caspase-3.

Main Methods:

  • 3D reconstruction of the apoptosome without symmetry restraints.
  • Analysis of caspase recruitment domains (CARDs) and catalytic domains.
  • Investigation of linker roles in procaspase-9 activation.

Main Results:

  • Evidence for a CARD-CARD disk formed by PC-9 and Apaf-1, tethered to the apoptosome.
  • A novel asymmetric proteolysis machine formed by disk assembly and PC-9 binding.
  • Identification of critical roles for CARD-p20 and p20-p10 linkers in PC-9 activation.
  • Overlapping binding sites for PC-9 and caspase-3 on the apoptosome's central hub.

Conclusions:

  • A proximity-induced association model for PC-9 activation on the apoptosome is proposed.
  • Overlapping binding sites suggest potential for hybrid apoptosomes with combined proteolytic activities.

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