Solution Structure of Apoptotic BAX Oligomer: Oligomerization Likely Precedes Membrane Insertion

Sung, Tai-Ching; Li, Ching-Yu; Lai, Yei‐Chen; Hung, Chien‐Lun; Shih, Orion; Yeh, Yi‐Qi; Chiang, Yun‐Wei

doi:10.1016/j.str.2015.07.013

Cited by 35 publications

(60 citation statements)

References 45 publications

(73 reference statements)

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“…In contrast to our results, the existence of soluble Bax homo-dimers and oligomers was recently reported 63, 64 . Garner et al 63 detected autoinhibited Bax homo-dimers in the cytosol of the cell extracts of a number of cell lines, whereas in other cell lines, no Bax homo-dimers were found, suggesting that a very specific regulation might be necessary.…”

Section: Discussioncontrasting

confidence: 99%

Quantitative interactome of a membrane Bcl-2 network identifies a hierarchy of complexes for apoptosis regulation

et al. 2017

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The Bcl-2 proteins form a complex interaction network that controls mitochondrial permeabilization and apoptosis. The relative importance of different Bcl-2 complexes and their spatio-temporal regulation is debated. Using fluorescence cross-correlation spectroscopy to quantify the interactions within a minimal Bcl-2 network, comprised by cBid, Bax, and Bcl-xL, we show that membrane insertion drastically alters the pattern of Bcl-2 complexes, and that the C-terminal helix of Bcl-xL determines its binding preferences. At physiological temperature, Bax can spontaneously activate in a self-amplifying process. Strikingly, Bax also recruits Bcl-xL to membranes, which is sufficient to retrotranslocate Bax back into solution to secure membrane integrity. Our study disentangles the hierarchy of Bcl-2 complex formation in relation to their environment: Bcl-xL association with cBid occurs in solution and in membranes, where the complex is stabilized, whereas Bcl-xL binding to Bax occurs only in membranes and with lower affinity than to cBid, leading instead to Bax retrotranslocation.

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Section: Discussioncontrasting

confidence: 99%

Quantitative interactome of a membrane Bcl-2 network identifies a hierarchy of complexes for apoptosis regulation

et al. 2017

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“…Recently, spectroscopic and scattering techniques have been used to identify the structures of the active Baxα monomer, dimer, and tetramer. These findings further support the concept that the displacement of helix α1 from the BH3-domain containing hydrophobic pocket is the first step for Baxα activation, leading to oligomerization and mitochondrial translocation (34). …”

Section: Introductionsupporting

confidence: 82%

“…Whether combination of fast degradation and association with other proteins can withhold BaxΔ2 activity under endogenous expression conditions remains to be explored. Another interesting notion is that, although active Baxα proteins can form oligomers in cytosol (34), they do not form large aggregates. This is most likely because Baxα proteins immediately translocate to mitochondria upon activation.…”

Section: Discussionmentioning

confidence: 99%

“…The Baxα C-terminal region has a transmembrane domain (TM) contained in helix α9 (15, 34, 40, 41), which has been reported to play a critical role in targeting (2, 31, 42, 43), anchoring, and penetrating the mitochondrial membrane (40, 44–46). However, it has also been shown that alteration or deletion of the C-terminal region has little influence on the ability of Baxα to target mitochondria (22, 25, 47–50) or its pro-apoptotic activity (25, 47, 48, 50).…”

Section: Introductionmentioning

confidence: 99%

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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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“…In this state, the protein either lays partially embedded on one side of the membrane, or traverses a lipidic pore possibly equivalent to the Bax apoptotic pore. This “unhinged” hypothesis has subsequently been supported by evidence from several groups and confirmed for Bak (Bleicken et al, 2014; Brouwer et al, 2014; Sung et al, 2015). Furthermore, structures of unhinged monomers within domain-swap dimers have been described for other Bcl-2 family members (Lee et al, 2011; O’Neill et al, 2006).…”

Section: Impact Of Bcl-2 Family Proteins On Mitochondria-like Membmentioning

confidence: 55%

Connecting mitochondrial dynamics and life-or-death events via Bcl-2 family proteins

Aouacheria

Baghdiguian

Lamb

et al. 2017

Neurochemistry International

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The morphology of a population of mitochondria is the result of several interacting dynamical phenomena, including fission, fusion, movement, elimination and biogenesis. Each of these phenomena is controlled by underlying molecular machinery, and when defective can cause disease. New understanding of the relationships between form and function of mitochondria in health and disease is beginning to be unraveled on several fronts. Studies in mammals and model organisms have revealed that mitochondrial morphology, dynamics and function appear to be subject to regulation by the same proteins that regulate apoptotic cell death. One protein family that influences mitochondrial dynamics in both healthy and dying cells is the Bcl-2 protein family. Connecting mitochondrial dynamics with life-death pathway forks may arise from the intersection of Bcl-2 family proteins with the proteins and lipids that determine mitochondrial shape and function. Bcl-2 family proteins also have multifaceted influences on cells and mitochondria, including calcium handling, autophagy and energetics, as well as the subcellular localization of mitochondrial organelles to neuronal synapses. The remarkable range of physical or functional interactions by Bcl-2 family proteins is challenging to assimilate into a cohesive understanding. Most of their effects may be distinct from their direct roles in apoptotic cell death and are particularly apparent in the nervous system. Dual roles in mitochondrial dynamics and cell death extend beyond BCL-2 family proteins. In this review, we discuss many processes that govern mitochondrial structure and function in health and disease, and how Bcl-2 family proteins integrate into some of these processes.

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Solution Structure of Apoptotic BAX Oligomer: Oligomerization Likely Precedes Membrane Insertion

Cited by 35 publications

References 45 publications

Quantitative interactome of a membrane Bcl-2 network identifies a hierarchy of complexes for apoptosis regulation

Quantitative interactome of a membrane Bcl-2 network identifies a hierarchy of complexes for apoptosis regulation

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

Connecting mitochondrial dynamics and life-or-death events via Bcl-2 family proteins

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