The apaf-1•procaspase-9 apoptosome complex functions as a proteolytic-based molecular timer
Malladi, Srinivas Challa-Malladi, Madhavi Fearnhead, Howard O Bratton, Shawn B
Malladi, Srinivas
Challa-Malladi, Madhavi
Fearnhead, Howard O
Bratton, Shawn B
Publication Date
2009-06-04
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Article
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Malladi, Srinivas; Challa-Malladi, Madhavi; Fearnhead, Howard O; Bratton, Shawn B (2009). The apaf-1•procaspase-9 apoptosome complex functions as a proteolytic-based molecular timer. The EMBO Journal 28 (13), 1916-1925
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 auto-processing 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. The EMBO Journal (2009) 28, 1916-1925. doi:10.1038/emboj.2009.152; Published online 4 June 2009
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Wiley-Blackwell
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Attribution-NonCommercial-NoDerivs 3.0 Ireland