Scientific Background | BAK is one of the two pore-forming effectors of mitochondrial apoptosis. Unlike BAX, it sits constitutively in the mitochondrial outer membrane, which means the cell cannot control it by keeping it in the cytosol and must instead restrain it through direct binding. This product spans the BAK BH3 domain, the helix through which that restraint is applied. The binding partners are specific rather than interchangeable, and that is what makes this particular peptide useful. Willis and colleagues showed that BAK is sequestered by MCL-1 and BCL-xL but not by BCL-2, and is released when BH3-only proteins displace it. A BAK BH3 peptide therefore reports on MCL-1 and BCL-xL engagement in a way that a BAX or BAD peptide does not, and in BH3 profiling it is the reagent used to ask whether a cell is leaning on those two proteins for survival. Truncated BID has separately been shown to oligomerise BAK directly to release cytochrome c, placing the domain at the point where an upstream signal becomes irreversible. Practically, this peptide is chosen when the question is MCL-1 or BCL-xL dependence, for example when profiling a cell line for likely sensitivity to an MCL-1 inhibitor. Pair it with a BAD BH3 peptide, which reads BCL-2 and BCL-xL but not MCL-1, to separate the contributions. |
References | 1. Willis SN, Chen L, Dewson G, et al. Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes & Development (2005) 19:1294. Genes Dev 2005;19:1294 2. Wei MC, Lindsten T, Mootha VK, et al. tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes & Development (2000) 14:2060. Genes Dev 2000;14:2060 3. BH3 profiling: a functional assay to measure apoptotic priming and dependencies. Methods in Molecular Biology (2019). PMID 30535998 |
