B-cell lymphoma 2 (Bcl-2) family protein-protein interfaces (Bcl-2 family PPIs)

The B-cell lymphoma 2 (Bcl-2) family protein-protein interfaces are critical regulatory sites that govern the intrinsic pathway of apoptosis (Adams & Cory, 2018). These interfaces involve the interaction between the BH3 (Bcl-2 homology 3) domain of pro-apoptotic proteins and a hydrophobic binding groove on anti-apoptotic members such as Bcl-2, Bcl-xL, and Mcl-1 (Letai, 2017). In many cancers, anti-apoptotic proteins are overexpressed, allowing the cell to evade programmed death by sequestering pro-apoptotic "activators" or "effectors" like Bax and Bak (Delbridge et al., 2016). Therapeutic intervention focuses on "BH3 mimetics," small molecules designed to occupy these grooves with high affinity, thereby displacing pro-apoptotic proteins to trigger mitochondrial outer membrane permeabilization (MOMP) and subsequent cell death (Montero & Letai, 2018). Venetoclax, a selective Bcl-2 inhibitor, represents the clinical success of targeting these interfaces, particularly in hematologic malignancies like chronic lymphocytic leukemia (Cymbalista et al., 2022).

Other names

Bcl-2 family proteinsBH3-binding groovesBcl-2 family regulatory complexBH3-only protein binding sites

BH3 mimetics competitively bind to the hydrophobic BH3-binding groove of anti-apoptotic Bcl-2 family members, preventing the sequestration of pro-apoptotic proteins and facilitating mitochondrial outer membrane permeabilization (MOMP) and apoptosis (Adams & Cory, 2018; Letai, 2017).