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BIM-Mediated Membrane Insertion of the BAK Pore Domain Is an Essential Requirement for Apoptosis

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journal contribution
posted on 09.07.2015, 11:09 by K. Weber, N. Harper, John W. R. Schwabe, G. M. Cohen
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.

History

Citation

Cell Reports, 2013, 5 (2), pp. 409-420

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Biological Sciences/Department of Biochemistry

Version

VoR (Version of Record)

Published in

Cell Reports

Publisher

Elsevier (Cell Press)

eissn

2211-1247

Acceptance date

06/09/2013

Copyright date

2013

Available date

09/07/2015

Publisher version

http://www.sciencedirect.com/science/article/pii/S2211124713005184

Notes

PMCID: PMC3898696

Language

en