<scp>BH</scp>
            3‐in‐groove dimerization initiates and helix 9 dimerization expands Bax pore assembly in membranes

Zhang, Zhi; Subramaniam, Sabareesh; Kale, Justin; Liao, Chenyi; Huang, Bo; Brahmbhatt, Hetal; Condon, Samson G.F.; Lapolla, Suzanne M.; Hays, Franklin A.; Ding, Jingzhen; He, Feng; Zhang, Xuejun C.; Li, Jianing; Senes, Alessandro; Andrews, David W.; Lin, Jialing

doi:10.15252/embj.201591552

Cited by 87 publications

(152 citation statements)

References 65 publications

(159 reference statements)

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“…Therefore, Bax dimers and oligomers could facilitate lateral sorting in the OMM or the formation of Bcl-2 protein-containing complexes (52). TMD-TMD interactions are consistent with models of Bax activation, suggesting separation of helices α5 and α6 (27,53) and the concerted insertion of both helices into the OMM (51,54). Conversely, Bax activation according to the clamp model would require a sequential mechanism to allow formation of antiparallel TMD interactions (28).…”

Section: Resultsmentioning

confidence: 61%

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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Section: Resultsmentioning

confidence: 61%

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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“…However, how BAK and BAX homodimers multimerize is unknown. From linkage or proximity measurements based on electroparamagnetic resonance and double electron-electron resonance various secondary interfaces have been implicated to allow homodimers to associate (23)(24)(25)(26)(27)(28). Alternatively, based on linkage analysis and mathematical modeling, random aggregation of homodimers has also been proposed (29).…”

mentioning

confidence: 99%

BAK α6 permits activation by BH3-only proteins and homooligomerization via the canonical hydrophobic groove

Tan

Stephen

et al. 2017

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

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BAK and BAX are the essential effectors of apoptosis because without them a cell is resistant to most apoptotic stimuli. BAK and BAX undergo conformation changes to homooligomerize then permeabilize the mitochondrial outer membrane during apoptosis. How BCL-2 homology 3 (BH3)-only proteins bind to activate BAK and BAX is unclear. We report that BH3-only proteins bind inactive full-length BAK at mitochondria and then dissociate following exposure of the BAK BH3 and BH4 domains before BAK homodimerization. Using a functional obstructive labeling approach, we show that activation of BAK involves important interactions of BH3-only proteins with both the canonical hydrophobic binding groove (α2-5) and α6 at the rear of BAK, with interaction at α6 promoting an open groove to receive a BH3-only protein. Once activated, how BAK homodimers multimerize to form the putative apoptotic pore is unknown. Obstructive labeling of BAK beyond the BH3 domain and hydrophobic groove did not inhibit multimerization and mitochondrial damage, indicating that critical protein-protein interfaces in BAK self-association are limited to the α2-5 homodimerization domain.AK and BAX are the pivotal effectors of intrinsic apoptosis, with one or the other being required for mitochondrial damage and cell death (1, 2). They are activated by interaction with BCL-2 homology 3 (BH3)-only proteins including BID and BIM (3). Structures show that peptides based on the BH3 domains of activator BH3-only proteins can bind directly to BAK and BAX via a hydrophobic groove (comprising α-helices 2-5) that is also shared with their prosurvival homologs (4-8). BAX has been proposed to have an additional activation site, distinct from the hydrophobic groove, at the rear of the molecule comprising α-helices 1 and 6 (9). Binding of stapled BH3 peptides at this site induced the dissociation of the BAX C-terminal transmembrane domain from the hydrophobic groove to facilitate mitochondrial localization (10, 11). Interaction of BH3-only proteins at this noncanonical site is not thought to be necessary for BAK activity because BAK is constitutively anchored in the mitochondrial outer membrane (MOM) via its transmembrane domain (12). However, recent reports that both BAX (13, 14) and BAK (15) are constantly "retrotranslocated" from the mitochondria to the cytosol suggest conserved mechanisms of activation for BAK and BAX.Characterizing the interaction of BH3-only proteins with fulllength BAK at mitochondria has proven difficult because the bound BH3-only protein dissociates during consequent BAK conformation changes, including exposure of the N-terminus (amino terminus) and and dissociation of their α2-5 helices ("core") from their α6-8 helices ("latch") (6, 7) to facilitate selfassociation. Additionally, structural studies have been largely confined to truncated protein or peptides in the absence of a membrane where interactions between BH3-only proteins and BAK occur.Once activated BAK and BAX self-associate to form pores that damage the MOM to release cytochrome c and...

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“…A new interface for Bax dimerization was identified which occurs via the α9:α9 helices within the membrane apart from the BH3:groove interface found on the surface, which was shown to be crucial for pore expansion (Zhang et al 2015). From this study, the discovery of another feature required for Bax dimerization has demonstrated that studies on the dynamics of protein structure and interactions are required to fully understand apoptosis at the dynamic membrane interface.…”

Section: Mode 1 Inhibiɵonmentioning

confidence: 93%

“…Upon α9 membrane insertion, rearrangement of the helices resulted in the BH3-in-groove dimerization at the MOM surface. The α9 helix that transverses the membrane interacts with α9 of another monomer to cause the pore expansion (Zhang et al 2015). These conformational changes were only able to be observed in the presence of membrane, thus emphasizing the importance of the membrane for the whole MOMP process.…”

Section: Biophysical Analysis Of the Apoptotic Pore Structural Modelsmentioning

confidence: 97%

“…The importance of studying protein activity at the membrane level was further demonstrated by a recent study by Zhang et al (2015). A new interface for Bax dimerization was identified which occurs via the α9:α9 helices within the membrane apart from the BH3:groove interface found on the surface, which was shown to be crucial for pore expansion (Zhang et al 2015).…”

Section: Mode 1 Inhibiɵonmentioning

confidence: 99%

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Mitochondrial outer membrane permeabilization: a focus on the role of mitochondrial membrane structural organization

et al. 2017

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Apoptosis is important in regulating cell death turnover and is mediated by the intrinsic and death receptor-based extrinsic pathways which converge at the mitochondrial outer membrane (MOM) leading to mitochondrial outer membrane permeabilization (MOMP). MOMP results in the release of apoptotic proteins that further activate the downstream pathway of apoptosis. Thus, tight regulation of MOMP is crucial in controlling apoptosis, and a lack of control may lead to tissue and organ malformation and the development of cancers. Despite a growing number of studies focusing on the structure and activity of the proteins involved in mediating MOMP, such as the Bcl-2 family proteins, the mechanism of MOMP is not well understood. In particular, the crucial role of the various structural properties and changes in lipid components of the MOM in mediating the recruitment and activation of different Bcl-2 proteins remains poorly understood. Furthermore, the factors that control the changes in mitochondrial membrane integrity from the initiation to the final disruption of MOM have yet to be clearly defined. In this review, we provide an overview of studies that focus on the mitochondrial membrane with a biophysical analysis of the interactions of the Bcl-2 proteins with the mitochondrial membrane.

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BH 3‐in‐groove dimerization initiates and helix 9 dimerization expands Bax pore assembly in membranes

Cited by 87 publications

References 65 publications

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

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

BAK α6 permits activation by BH3-only proteins and homooligomerization via the canonical hydrophobic groove

Mitochondrial outer membrane permeabilization: a focus on the role of mitochondrial membrane structural organization

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