dc.contributor.author | Malladi, Srinivas | |
dc.contributor.author | Challa-Malladi, Madhavi | |
dc.contributor.author | Fearnhead, Howard O | |
dc.contributor.author | Bratton, Shawn B | |
dc.date.accessioned | 2018-09-20T16:15:45Z | |
dc.date.available | 2018-09-20T16:15:45Z | |
dc.date.issued | 2009-06-04 | |
dc.identifier.citation | 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 | |
dc.identifier.issn | 0261-4189,1460-2075 | |
dc.identifier.uri | http://hdl.handle.net/10379/12614 | |
dc.description.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 | |
dc.publisher | Wiley-Blackwell | |
dc.relation.ispartof | The EMBO Journal | |
dc.rights | Attribution-NonCommercial-NoDerivs 3.0 Ireland | |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/3.0/ie/ | |
dc.subject | apaf-1 | |
dc.subject | caspase-9 | |
dc.subject | apoptosome | |
dc.subject | apoptosis | |
dc.subject | molecular timer | |
dc.subject | caspase-activating complex | |
dc.subject | cytochrome-c | |
dc.subject | nucleotide exchange | |
dc.subject | dependent formation | |
dc.subject | apaf-1 apoptosome | |
dc.subject | cancer cells | |
dc.subject | procaspase-9 | |
dc.subject | binding | |
dc.subject | inhibition | |
dc.subject | phosphorylation | |
dc.title | The apaf-1•procaspase-9 apoptosome complex functions as a proteolytic-based molecular timer | |
dc.type | Article | |
dc.identifier.doi | 10.1038/emboj.2009.152 | |
dc.local.publishedsource | http://emboj.embopress.org/content/embojnl/28/13/1916.full.pdf | |
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