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Related Experiment Videos

The apoptosome activates caspase-9 by dimerization.

Cristina Pop1, John Timmer, Sabina Sperandio

  • 1Program in Apoptosis and Cell Death Research, The Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.

Molecular Cell
|April 25, 2006
PubMed
Summary
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Apical caspases like caspase-9 are activated by dimerization on the apoptosome platform. This induced proximity model explains caspase activation, ruling out allosteric mechanisms for apoptosis.

Area of Science:

  • Cellular biology
  • Biochemistry
  • Molecular mechanisms of apoptosis

Background:

  • Caspase-9, an apical protease in intrinsic apoptosis, activates on the apoptosome.
  • Two models exist for caspase-9 activation: allosteric activation or dimer-driven assembly (induced proximity).

Purpose of the Study:

  • To elucidate the activation mechanism of caspase-9 on the apoptosome.
  • To differentiate between allosteric and induced proximity models of caspase activation.

Main Methods:

  • Utilized Hofmeister salts and a reconstituted mini-apoptosome to study caspase-9 activation kinetics.
  • Employed protein engineering by replacing the recruitment domain of caspase-8 with that of caspase-9.

Main Results:

Related Experiment Videos

  • Caspase-9 activation by both Hofmeister salts and mini-apoptosome followed a second-order process, consistent with dimer-driven assembly.
  • A hybrid caspase-8/9 construct demonstrated apoptosome-mediated activation, indicating recruitment is sufficient.

    • Conclusions:

    • The findings support a conserved dimer-driven, induced proximity model for apical caspase activation.
    • Apical caspase activation on the apoptosome does not require allosteric mechanisms, but rather proximity-induced dimerization.