A Unified Model of Mammalian BCL-2 Protein Family Interactions at the Mitochondria

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2011 Nov 1

PMID 22036586

Citations 308

Authors

Fabien Llambi

Tudor Moldoveanu

Stephen W G Tait

Lisa Bouchier-Hayes

Jamshid Temirov

Laura L McCormick

Christopher P Dillon

Douglas R Green

Affiliations

Soon will be listed here.

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.

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