LIG_BH_BH3_1

Apoptosis or Programmed Cell Death is an evolutionarily conserved process that plays an important role in the removal of infected, damaged, or unwanted cells. Dysregulation of this process can lead to a variety of disorders, including neurodegenerative diseases and cancer. The Bcl-2 family proteins function upstream of caspases as regulators of ‘life-or-death’ decisions in response to various intrinsic and extrinsic stimuli.They are characterized by the presence of conserved sequence motifs known as Bcl-2 homology domains (BH1-BH4). In addition to BH domains, they frequently have a hydrophobic C-terminal part that is important for localization to the mitochondrial outer membrane (MOM), endoplasmic reticulum (ER) and the nuclear envelope (Petros,2004). Members of the Bcl-2 family are grouped into pro- and anti-apoptotic proteins. The anti-apoptotic proteins contain all four BH domains. The pro-apoptotic group contains two subgroups: (i) the multi-domain (BH1-3) containing proteins, and (ii) the single BH3 motif containing proteins. This BH3 motif is required for the killing activity of these pro-apoptotic proteins (Lomonosova,2009).
Different BH3-only proteins sense different stress condition and in response promote apoptosis by binding to and regulating anti-apoptotic Bcl-2 family proteins. The anti-apoptotic Bcl-2 proteins prevent apoptosis either by sequestering activator BH3-only proteins tBID-BIM-PUMA-NOXA thereby preventing them from activating BAX-BAK, or by sequestering partially activated, BH3-exposed monomeric BAX-BAK to prevent their homo-oligomerization (Chen,2015). Many theories have been postulated to explain how BH3 domains regulate apoptosis. In general, to initiate apoptosis, all pro-survival proteins must be neutralized by the BH3-only proteins, then the activator BH3 proteins promote BAX/BAK to undergo oligomerization and insert into the mitochondrial outer membrane, resulting in mitochondrial outer membrane permeabilization (MOMP). As a consequence of MOMP, apoptogenic particles are released from the mitochondria and the regulated disintegration of the cell is initiated (17306210).
The BH3-only proteins are generally promiscuous binders. While some bind all anti-apoptotic proteins with nearly equal affinity, others have differential binding specificity and affinity (Chen,2005). The interaction between the pro- and anti-apoptotic members is mediated through a hydrophobic cleft formed by the BH1-3 domains of anti-apoptotic members and the BH3 motifs of pro-apoptotic proteins. The BH3 motif folds into an amphipathic helix in the hydrophobic groove of the anti-apoptotic proteins upon binding (Petros,2004). The generalized BH3 motif has a consensus pattern of ….[LIFVYME][ASGC][^P]{2}L[^P]{2}[IVMTL][GACS][D][^P][FVLMI]. Viral BH3-containing proteins were also found to regulate apoptosis in infected host cells and manipulate it to their own advantage (Mohd-Ismail,2009).
BH-BH3 interactions are considered to be highly promising targets for protein-protein interaction inhibition. Small molecules inhibitors of BCL-2, such as ABT-199, are expected to play a role in cancer therapy, provided that unwanted side effects can be controlled (Davids,2013).