1. Conversion of Bim-BH3 from Activator to Inhibitor of Bak through Structure-Based Design
Ahmad Wardak, Iris K Tan, Boris Reljic, Brad E Sleebs, Brian J Smith, Jonathan P Bernardini, Angus D Cowan, Peter M Colman, Ping Lan, Erinna F Lee, Melissa J Call, Peter E Czabotar, Adeline Y Robin, Mark F van Delft, Jason M Brouwer, Grant Dewson, W Douglas Fairlie, Guillaume Lessene, Richard W Birkinshaw Mol Cell . 2017 Nov 16;68(4):659-672.e9. doi: 10.1016/j.molcel.2017.11.001.
Certain BH3-only proteins transiently bind and activate Bak and Bax, initiating their oligomerization and the permeabilization of the mitochondrial outer membrane, a pivotal step in the mitochondrial pathway to apoptosis. Here we describe the first crystal structures of an activator BH3 peptide bound to Bak and illustrate their use in the design of BH3 derivatives capable of inhibiting human Bak on mitochondria. These BH3 derivatives compete for the activation site at the canonical groove, are the first engineered inhibitors of Bak activation, and support the role of key conformational transitions associated with Bak activation.
2. BCL-2 proteins and apoptosis: Recent insights and unknowns
Frank Edlich Biochem Biophys Res Commun . 2018 May 27;500(1):26-34. doi: 10.1016/j.bbrc.2017.06.190.
Proteins of the B-cell lymphoma-2 (BCL-2) family control the intrinsic apoptosis pathway. The pro-apoptotic BCL-2 proteins BAX and BAK can commit a cell to its programmed death by permeabilizing the outer mitochondrial membrane (OMM) and subsequent initiation of the caspase cascade. Therefore, the activities of BAX and BAK are precisely controlled by a complex network of proteins inside and outside the BCL-2 family. Cells survive by constant control of dynamic translocation and retrotranslocation of BAX and BAK to the mitochondria and back into the cytosol. Recent insights into BAX/BAK shuttling, BCL-2 protein interactions, the role of BH3-only proteins in apoptosis signaling and the active BAX complex set the stage for the development of novel strategies in cancer therapy and the analysis of cellular predisposition to apoptosis.
3. BH3-only proteins target BCL-xL/MCL-1, not BAX/BAK, to initiate apoptosis
Liqiang Zhang, Kai Huang, Na Han, Lucas Struble, Zhaorui Liu, Wei Wu, Xu Luo, Wei Zhou, Gloria Borgstahl, Jian Li, Katelyn L O'Neill, Xiaming Pang Cell Res . 2019 Nov;29(11):942-952. doi: 10.1038/s41422-019-0231-y.
It has been widely accepted that mitochondria-dependent apoptosis initiates when select BH3-only proteins (BID, BIM, etc.) directly engage and allosterically activate effector proteins BAX/BAK. Here, through reconstitution of cells lacking all eight pro-apoptotic BH3-only proteins, we demonstrate that all BH3-only proteins primarily target the anti-apoptotic BCL-2 proteins BCL-xL/MCL-1, whose simultaneous suppression enables membrane-mediated spontaneous activation of BAX/BAK. BH3-only proteins' apoptotic activities correlate with affinities for BCL-xL/MCL-1 instead of abilities to directly activate BAX/BAK. Further, BID and BIM do not distinguish BAX from BAK or accelerate BAX/BAK activation following inactivation of BCL-xL/MCL-1. Remarkably, death ligand-induced apoptosis in cells lacking BH3-only proteins and MCL-1 is fully restored by BID mutants capable of neutralizing BCL-xL, but not direct activation of BAX/BAK. Taken together, our findings provide a "Membrane-mediated Permissive" model, in which the BH3-only proteins only indirectly activate BAX/BAK by neutralizing the anti-apoptotic BCL-2 proteins, and thus allowing BAX/BAK to undergo unimpeded, spontaneous activation in the mitochondrial outer membrane milieu, leading to apoptosis initiation.
