Please use this identifier to cite or link to this item:
|Title:||BIM-Mediated Membrane Insertion of the BAK Pore Domain Is an Essential Requirement for Apoptosis|
Schwabe, John W. R.
Cohen, G. M.
|Publisher:||Elsevier (Cell Press)|
|Citation:||Cell Reports, 2013, 5 (2), pp. 409-420|
|Abstract:||BAK activation represents a key step during apoptosis, but how it converts into a mitochondria-permeabilizing pore remains unclear. By further delineating the structural rearrangements involved, we reveal that BAK activation progresses through a series of independent steps: BH3-domain exposure, N-terminal change, oligomerization, and membrane insertion. Employing a "BCL-XL-addiction" model, we show that neutralization of BCL-XL by the BH3 mimetic ABT-737 resulted in death only when cells were reconstituted with BCL-XL:BAK, but not BCL-2/ BCL-XL:BIM complexes. Although this resembles the indirect model, release of BAK from BCL-XL did not result in spontaneous adoption of the pore conformation. Commitment to apoptosis required association of the direct activator BIM with oligomeric BAK promoting its conversion to a membrane-inserted pore. The sequential nature of this cascade provides multiple opportunities for other BCL-2 proteins to interfere with or promote BAK activation and unites aspects of the indirect and direct activation models.|
|Rights:||Copyright © the authors, 2013. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License (http://creativecommons.org/licenses/by-nc-nd/3.0/ ), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.|
|Appears in Collections:||Published Articles, College of Medicine, Biological Sciences and Psychology|
Files in This Item:
|1-s2.0-S2211124713005184-main.pdf||Published (publisher PDF)||1.9 MB||Adobe PDF||View/Open|
Items in LRA are protected by copyright, with all rights reserved, unless otherwise indicated.