A unified model of mammalian BCL-2 protein family interactions at the mitochondria

Llambi, F., Moldoveanu, T., Tait, S.W.G. , Bouchier-Hayes, L., Temirov, J., McCormick, L.L., Dillon, C.P. and Green, D.R. (2011) A unified model of mammalian BCL-2 protein family interactions at the mitochondria. Molecular Cell, 44(4), pp. 517-531. (doi:10.1016/j.molcel.2011.10.001)

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Abstract

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Tait, Professor Stephen
Authors: Llambi, F., Moldoveanu, T., Tait, S.W.G., Bouchier-Hayes, L., Temirov, J., McCormick, L.L., Dillon, C.P., and Green, D.R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Molecular Cell
Journal Abbr.:Mol. Cell.
ISSN:1097-2765
ISSN (Online):1097-4164
Published Online:27 October 2011

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