Exposure of mammalian cells to apoptotic stress promotes the translocation of the pro-apoptotic protein BCL-2-associated X (BAX) from the cytosol to the mitochondria, in parallel with a conformational transition from a monomer to an oligomer. Oligomeric BAX permeabilizes the mitochondrial outer membrane and releases cytochrome c to initiate apoptosis. BAX-mediated apoptosis can be inhibited through heterodimeric interactions between anti-apoptotic members of the BCL-2 family and BAX. However, higher order complexes were initially refractory to structural characterization owing to protein heterogeneity. Previous work from this group used a specific detergent, Fos-12, to isolate a homogeneous BAX oligomer (BAXo) that was resistant to the inhibitory effects of monomeric anti-apoptot…
Exposure of mammalian cells to apoptotic stress promotes the translocation of the pro-apoptotic protein BCL-2-associated X (BAX) from the cytosol to the mitochondria, in parallel with a conformational transition from a monomer to an oligomer. Oligomeric BAX permeabilizes the mitochondrial outer membrane and releases cytochrome c to initiate apoptosis. BAX-mediated apoptosis can be inhibited through heterodimeric interactions between anti-apoptotic members of the BCL-2 family and BAX. However, higher order complexes were initially refractory to structural characterization owing to protein heterogeneity. Previous work from this group used a specific detergent, Fos-12, to isolate a homogeneous BAX oligomer (BAXo) that was resistant to the inhibitory effects of monomeric anti-apoptotic proteins, raising questions about the potential regulation of BAXo. Newman et al. used a similar protocol to identify a full-length, symmetric dimer of anti-apoptotic BCL-w, called BCL-wD, which they characterized by small-angle X-ray scattering (SAXS), molecular dynamics simulations and hydrogen–deuterium exchange mass spectrometry (HDX-MS). Direct interaction of BCL-wD with BAXo was sufficient to dissociate BAXo and block cytochrome c release from mitochondria. HDX-MS and cross-linking analyses revealed the precise conformational changes and contact points that regulate the oligomeric and membrane interfaces of BAXo. SAXS analyses of lipid systems further showed that BAXo induced negative Gaussian curvature to disrupt membrane integrity, whereas BCL-wD blocked this effect by promoting positive Gaussian curvature, revealing opposing effects on the mitochondrial outer membrane itself. Overall, the findings reveal that BCL-2 family proteins modulate cell death by a complex interplay between not only pro- and anti-apoptotic monomers but also dueling multimers.
Original reference: Cell https://doi.org/10.1016/j.cell.2025.10.037 (2025)
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Miura, G. Dueling multimers. Nat Chem Biol (2025). https://doi.org/10.1038/s41589-025-02116-7
Published: 22 December 2025
Version of record: 22 December 2025
DOI: https://doi.org/10.1038/s41589-025-02116-7