The Apaf-1procaspase-9 apoptosome complex functions as a proteolytic-based molecular timer

Srinivas Malladi, Madhavi Challa-Malladi, Howard O. Fearnhead, Shawn B. Bratton

Research output: Contribution to journalArticle

91 Scopus citations

Abstract

During stress-induced apoptosis, the initiator caspase-9 is activated by the Apaf-1 apoptosome and must remain bound to retain significant catalytic activity. Nevertheless, in apoptotic cells the vast majority of processed caspase-9 is paradoxically observed outside the complex. We show herein that apoptosome-mediated cleavage of procaspase-9 occurs exclusively through a CARD-displacement mechanism, so that unlike the effector procaspase-3, procaspase-9 cannot be processed by the apoptosome as a typical substrate. Indeed, procaspase-9 possessed higher affinity for the apoptosome and could displace the processed caspase-9 from the complex, thereby facilitating a continuous cycle of procaspase-9 recruitment/activation, processing, and release from the complex. Owing to its rapid autocatalytic cleavage, however, procaspase-9 per se contributed little to the activation of procaspase-3. Thus, the Apaf-1 apoptosome functions as a proteolytic-based molecular timer, wherein the intracellular concentration of procaspase-9 sets the overall duration of the timer, procaspase-9 autoprocessing activates the timer, and the rate at which the processed caspase-9 dissociates from the complex (and thus loses its capacity to activate procaspase-3) dictates how fast the timer ticks over.

Original languageEnglish (US)
Pages (from-to)1916-1925
Number of pages10
JournalEMBO Journal
Volume28
Issue number13
DOIs
StatePublished - Jul 8 2009

Keywords

  • Apaf-1
  • Apoptosis
  • Apoptosome
  • Caspase-9
  • Molecular timer

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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