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Title: BIM-Mediated Membrane Insertion of the BAK Pore Domain Is an Essential Requirement for Apoptosis
Authors: Weber, K.
Harper, N.
Schwabe, John W. R.
Cohen, G. M.
First Published: 10-Oct-2013
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.
DOI Link: 10.1016/j.celrep.2013.09.010
eISSN: 2211-1247
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
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 ( ), 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.
Description: PMCID: PMC3898696
Appears in Collections:Published Articles, College of Medicine, Biological Sciences and Psychology

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