Bax monomers form dimer units in the membrane that further self-assemble into multiple oligomeric species

Subburaj, Yamunadevi; Cosentino, Katia; Axmann, Markus; Pedrueza‐Villalmanzo, Esteban; Hermann, Eduard; Bleicken, Stephanie; Spatz, Joachim P.; García‐Sáez, Ana J.

doi:10.1038/ncomms9042

Cited by 156 publications

(198 citation statements)

References 60 publications

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“…Our results suggest that α9 is the trigger site of Bax/ Bak and that a stable interaction between α9 and the OMM is sufficient to initiate the series of conformational changes and homo-oligomerization. Consistent with this conclusion, a recent study with reconstituted membranes suggested that, once in the membrane, Bax molecules form dimers, which further self-assemble into homo-oligomers (Subburaj et al 2015). Furthermore, an α9-α9 interface was recently detected in the homo-oligomers of Bax and Bak (Bleicken et al 2014;Gahl et al 2014;Iyer et al 2015).…”

Section: Omm As the Direct Activator Of Bax/bak Following Neutralizatsupporting

confidence: 67%

Inactivation of prosurvival Bcl-2 proteins activates Bax/Bak through the outer mitochondrial membrane

et al. 2016

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The mechanism of Bax/Bak activation remains a central question in mitochondria-dependent apoptotic signaling. While it is established that all proapoptotic Bcl-2 homology 3 (BH3)-only proteins bind and neutralize the antiapoptotic Bcl-2 family proteins, how this neutralization leads to Bax/Bak activation has been actively debated. Here, genome editing was used to generate cells deficient for all eight proapoptotic BH3-only proteins (OctaKO) and those that lack the entire Bcl-2 family (Bcl-2 allKO). Although the OctaKO cells were resistant to most apoptotic stimuli tested, they underwent Bax/Bak-dependent and p53/Rb-independent apoptosis efficiently when both Bcl-xL and Mcl-1, two anti-apoptotic Bcl-2 proteins, were inactivated or eliminated. Strikingly, when expressed in the Bcl-2 allKO cells, both Bax and Bak spontaneously associated with the outer mitochondrial membrane (OMM) through their respective helix 9, and this association triggered their homo-oligomerization/activation. Together, these results strongly suggest that the OMM, not BH3-only proteins or p53/Rb, is the long-sought-after direct activator of Bax/Bak following BH3-only-mediated neutralization of anti-apoptotic Bcl-2 proteins.

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Section: Omm As the Direct Activator Of Bax/bak Following Neutralizatsupporting

confidence: 67%

Inactivation of prosurvival Bcl-2 proteins activates Bax/Bak through the outer mitochondrial membrane

et al. 2016

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“…Regulatory interactions between Bax and other Bcl-2 proteins can only be observed in the presence of the OMM or liposomes (17,18). Recent studies suggest that Bax is inserted in mitochondrial membranes as a monomer that oligomerizes once inserted (19)(20)(21). These studies also have shown that Bcl-x L inhibits Bax by dissociating Bax oligomers.…”

mentioning

confidence: 68%

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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“…The underlying mechanism is not fully understood, but it is believed that ART is responsible for maintaining the inactive monomeric form of Baxα proteins. Upon stimulation by cell death signals, Baxα monomers undergo conformational changes, form oligomers, and target mitochondria (26–33). Although the exact nature of the conformational changes is controversial, it is generally accepted that the death signal-induced exposure of the BH3 domain is critical for Baxα activation.…”

Section: Introductionmentioning

confidence: 99%

The functional domains for Bax∆2 aggregate-mediated caspase 8-dependent cell death

Mañas

Wang

Nelson

et al. 2017

Experimental Cell Research

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BaxΔ2 is a functional pro-apoptotic Bax isoform having alterations in its N-terminus, but sharing the rest of its sequence with Baxα. BaxΔ2 is unable to target mitochondria due to the loss of helix α1. Instead, it forms cytosolic aggregates and activates caspase 8. However, the functional domain(s) responsible for BaxΔ2 behavior have remained elusive. Here we show that disruption of helix α1 makes Baxα mimic the behavior of BaxΔ2. However, the other alterations in the BaxΔ2 N-terminus have no significant impact on aggregation or cell death. We found that the hallmark BH3 domain is necessary but not sufficient for aggregation-mediated cell death. We also noted that the core region shared by Baxα and BaxΔ2 is required for the formation of large aggregates, which is essential for BaxΔ2 cytotoxicity. However, aggregation by itself is unable to trigger cell death without the C-terminus. Interestingly, the C-terminal helical conformation, not its primary sequence, appears to be critical for caspase 8 recruitment and activation. As BaxΔ2 shares core and C-terminal sequences with most Bax isoforms, our results not only reveal a structural basis for BaxΔ2-induced cell death, but also imply an intrinsic potential for aggregate-mediated caspase 8-dependent cell death in other Bax family members.

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Bax monomers form dimer units in the membrane that further self-assemble into multiple oligomeric species

Cited by 156 publications

References 60 publications

Inactivation of prosurvival Bcl-2 proteins activates Bax/Bak through the outer mitochondrial membrane

Inactivation of prosurvival Bcl-2 proteins activates Bax/Bak through the outer mitochondrial membrane

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

The functional domains for Bax∆2 aggregate-mediated caspase 8-dependent cell death

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