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This Article Full Text Full Text (PDF) All Versions of this Article: 287/3/C664    most recent 00232.2003v2 00232.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (9) Citing Articles via Google Scholar Google Scholar Articles by Beem, E. Articles by Segal, M. S. Search for Related Content PubMed PubMed Citation Articles by Beem, E. Articles by Segal, M. S.

GROWTH, DIFFERENTIATION, AND APOPTOSIS

The 1.4-MDa apoptosome is a critical intermediate in apoptosome maturation

¹Division of Nephrology, Hypertension and Transplantation, Department of Medicine; and ²College of Dentistry, University of Florida, Gainesville, Florida 32610

Submitted 3 June 2003 ; accepted in final form 27 April 2004

Previously, we demonstrated that both 150 mM KCl and alkaline pH inhibit cytochrome c-mediated activation of procaspase-3 in a unique manner. To determine the mechanism of inhibition, we analyzed the effect of KCl and alkaline pH on the formation of apoptosomes (a large complex consisting of cytochrome c, Apaf-1, and procaspase-9/caspase-9) in vitro. Our results suggest that an initial 700-kDa apoptosome matures through a 1.4-MDa intermediate before a 700-kDa apoptosome is reformed and procaspase-3 is activated. We further demonstrate that 150 mM KCl interferes with the conversion of the initial 700-kDa apoptosome to the 1.4-MDa intermediate, while alkaline pH "traps" the apoptosome in the 1.4-MDa intermediate. Analysis of the cleaved state of procaspase-9 and procaspase-3 suggests that the 1.4-MDa intermediate may be required for cleavage of procaspase-9. Consistent with these results, in vivo data suggest that blocking acidification during the induction of apoptosis inhibits activation of procaspase-3. On the basis of these results, we propose a model of apoptosome maturation.

caspase; pH; potassium; apoptosis

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