The selective BH4-domain biology of Bcl-2-family members: IP3Rs and beyond

Anti-apoptotic Bcl-2-family members not only neutralize pro-apoptotic proteins but also directly regulate intracellular Ca2+ signaling from the endoplasmic reticulum (ER), critically controlling cellular health, survival, and death initiation. Furthermore, distinct Bcl-2-family members may selectively regulate inositol 1,4,5-trisphosphate receptor (IP3R): Bcl-2 likely acts as an endogenous inhibitor of the IP3R, preventing pro-apoptotic Ca2+ transients, while Bcl-X-L likely acts as an endogenous IP3R-sensitizing protein promoting pro-survival Ca2+ oscillations. Furthermore, distinct functional domains in Bcl-2 and Bcl-X-L may underlie the divergence in IP3R regulation. The Bcl-2 homology (BH) 4 domain, which targets the central modulatory domain of the IP3R, is likely to be Bcl-2's determining factor. In contrast, the hydrophobic cleft targets the C-terminal Ca2+-channel tail and might be more crucial for Bcl-X-L's function. Furthermore, one amino acid critically different in the sequence of Bcl-2's and Bcl-X-L's BH4 domains underpins their selective effect on Ca2+ signaling and distinct biological properties of Bcl-2 versus Bcl-X-L. This difference is evolutionary conserved across five classes of vertebrates and may represent a fundamental divergence in their biological function. Moreover, these insights open novel avenues to selectively suppress malignant Bcl-2 function in cancer cells by targeting its BH4 domain, while maintaining essential Bcl-X-L functions in normal cells. Thus, IP3R-derived molecules that mimic the BH4 domain's binding site on the IP3R may function synergistically with BH3-mimetic molecules selectivity suppressing Bcl-2's proto-oncogenic activity. Finally, a more general role for the BH4 domain on IP(3)Rs, rather than solely anti-apoptotic, may not be excluded as part of a complex network of molecular interactions.