The Bak core dimer focuses triacylglycerides in the membrane

Smith, Nicholas; Wardak, AZ; Cowan, AD; Colman, PM; Czabotar, PE; Smith, Brian

doi:10.1016/j.bpj.2021.12.043

The Bak core dimer focuses triacylglycerides in the membrane

https://doi.org/10.1016/j.bpj.2021.12.043
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journal contribution

posted on 2025-11-25, 22:49 authored by Nicholas SmithNicholas Smith, AZ Wardak, AD Cowan, PM Colman, PE Czabotar, Brian SmithBrian Smith

Apoptosis, the intrinsic programmed cell death process, is mediated by the Bcl-2 family members Bak and Bax. Activation via formation of symmetric core dimers and oligomerization on the mitochondrial outer membrane (MOM) leads to permeabilization and cell death. Although this process is linked to the MOM, the role of the membrane in facilitating such pores is poorly understood. We recently described Bak core domain dimers, revealing lipid binding sites and an initial role of lipids in oligomerization. Here we describe simulations that identified localized clustering and interaction of triacylglycerides (TAGs) with a minimized Bak dimer construct. Coalescence of TAGs occurred beneath this Bak dimer, mitigating dimer-induced local membrane thinning and curvature in representative coarse-grain MOM and model membrane systems. Furthermore, the effects observed as a result of coarse-grain TAG cluster formation was concentration dependent, scaling from low physiological MOM concentrations to those found in other organelles. We find that increasing the TAG concentration in liposomes mimicking the MOM decreased the ability of activated Bak to permeabilize these liposomes. These results suggest that the presence of TAGs within a Bak-lipid membrane preserves membrane integrity and is associated with reduced membrane stress, suggesting a possible role of TAGs in Bak-mediated apoptosis.<p></p>