Journal
MOLECULAR CELL
Volume 44, Issue 4, Pages 517-531Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2011.10.001
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Funding
- National Institutes of Health [AI40646, GM52735, GM096208]
- American Lebanese Syrian Associated Charities
- Sass Foundation for Medical Research
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During apoptosis, the BCL-2 protein family controls mitochondrial outer membrane permeabilization (MOMP), but the dynamics of this regulation remain controversial. We employed chimeric proteins composed of exogenous BH3 domains inserted into a tBID backbone that can activate the proapoptotic effectors BAX and BAK to permeabilize membranes without being universally sequestered by all antiapoptotic BCL-2 proteins. We thus identified two modes whereby prosurvival BCL-2 proteins can block MOMP, by sequestering direct-activator BH3-only proteins (MODE 1) or by binding active BAX and BAK (MODE 2). Notably, we found that MODE 1 sequestration is less efficient and more easily derepressed to promote MOMP than MODE 2. Further, MODE 2 sequestration prevents mitochondrial fusion. We provide a unified model of BCL-2 family function that helps to explain otherwise paradoxical observations relating to MOMP, apoptosis, and mitochondrial dynamics.
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