Bax Forms an Oligomer via Separate, Yet Interdependent, Surfaces

Zhang, Zhi; Zhu, Wenyi; Lapolla, Suzanne M.; Miao, Yiwei; Shao, Yuanlong; Falcone, Mina; Boreham, Doug; McFarlane, Nicole; Ding, Jingzhen; Johnson, Arthur E.; Zhang, Xuejun C.; Andrews, David W.; Lin, Jialing

doi:10.1074/jbc.m110.113456

Cited by 70 publications

(94 citation statements)

References 54 publications

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“…However, the structures of the domain-swapped dimers appear at odds with data on the interfaces in BAX oligomers formed during apoptosis [66][67][68] and incompatible with a model in which helices a5 and a6 insert into the membrane during permeabilization. The similarity of the BAXDC structures with pro-survival proteins, together with the facts that BAX inserts in membranes can form membrane pores as a monomer and is likely to unfold on the membrane (see below), indicate that swapped-dimer structures may not be directly involved in the activation pathway.…”

Section: Molecular Basis For Bcl-2 Family Protein Functioncontrasting

confidence: 39%

The rheostat in the membrane: BCL-2 family proteins and apoptosis

et al. 2013

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Apoptosis, a mechanism for programmed cell death, has key roles in human health and disease. Many signals for cellular life and death are regulated by the BCL-2 family proteins and converge at mitochondria, where cell fate is ultimately decided. The BCL-2 family includes both pro-life (e.g. BCL-XL) and pro-death (e.g. BAX, BAK) proteins. Previously, it was thought that a balance between these opposing proteins, like a simple 'rheostat', could control the sensitivity of cells to apoptotic stresses. Later, this rheostat concept had to be extended, when it became clear that BCL-2 family proteins regulate each other through a complex network of bimolecular interactions, some transient and some relatively stable. Now, studies have shown that the apoptotic circuitry is even more sophisticated, in that BCL-2 family interactions are spatially dynamic, even in nonapoptotic cells. For example, BAX and BCL-XL can shuttle between the cytoplasm and the mitochondrial outer membrane (MOM). Upstream signaling pathways can regulate the cytoplasmic-MOM equilibrium of BAX and thereby adjust the sensitivity of cells to apoptotic stimuli. Thus, we can view the MOM as the central locale of a dynamic life-death rheostat. BAX invariably forms extensive homo-oligomers after activation in membranes. However, recent studies, showing that activated BAX monomers determine the kinetics of MOM permeabilization (MOMP), perturb the lipid bilayer and form nanometer size pores, pose questions about the role of the oligomerization. Other lingering questions concern the molecular mechanisms of BAX redistribution between MOM and cytoplasm and the details of BAX/BAK-membrane assemblies. Future studies need to delineate how BCL-2 family proteins regulate MOMP, in concert with auxiliary MOM proteins, in a dynamic membrane environment. Technologies aimed at elucidating the structure and function of the full-length proteins in membranes are needed to illuminate some of these critical issues.

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Section: Molecular Basis For Bcl-2 Family Protein Functioncontrasting

confidence: 39%

The rheostat in the membrane: BCL-2 family proteins and apoptosis

et al. 2013

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“…The consistent picture that emerges from these studies is that Bcl-2 and Bcl-xL TMDs could have the ability to regulate Bax pore-forming activity by means of direct competition, leading to the formation of heterooligomers that abate Bax homooligomer formation and OMM permeabilization. The existence of Bax TMD interactions has been proposed based on cross-linking experiments (49,50) and 3D models (28) and has been suggested to contribute to the enlargement of the Bax pore (51). Although not as tight as hydrophobic groove and BH3 domain interactions, TMD-TMD interactions are sufficient for heterooligomerization and homooligomerization of Bcl-2 proteins.…”

Section: Resultsmentioning

confidence: 99%

Bax transmembrane domain interacts with prosurvival Bcl-2 proteins in biological membranes

Andreu-Férnández

Sancho

Genovés

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The Bcl-2 (B-cell lymphoma 2) protein Bax (Bcl-2 associated X, apoptosis regulator) can commit cells to apoptosis via outer mitochondrial membrane permeabilization. Bax activity is controlled in healthy cells by prosurvival Bcl-2 proteins. C-terminal Bax transmembrane domain interactions were implicated recently in Bax pore formation. Here, we show that the isolated transmembrane domains of Bax, Bcl-x L (B-cell lymphoma-extra large), and Bcl-2 can mediate interactions between Bax and prosurvival proteins inside the membrane in the absence of apoptotic stimuli. Bcl-2 protein transmembrane domains specifically homooligomerize and heterooligomerize in bacterial and mitochondrial membranes. Their interactions participate in the regulation of Bcl-2 proteins, thus modulating apoptotic activity. Our results suggest that interactions between the transmembrane domains of Bax and antiapoptotic Bcl-2 proteins represent a previously unappreciated level of apoptosis regulation.

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“…Because the ␣6 helix of Bak (and Bax) has an induced proximity during apoptosis, we proposed that an ␣6:␣6 interface may represent this secondary interface (22,24). In an alternative model, Bak/Bax oligomerize via a repeated asymmetric interface involving interaction of the BH3 domain from one molecule with a site involving the ␣6 or "rear pocket" on a partner molecule (25)(26)(27). In silico modeling suggested that this nose-to-tail association allows the formation of an octameric pore with a sufficient diameter to allow the passage of cytochrome c (28).…”

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confidence: 99%