Bcl-2-Protein Family as Modulators of IP3Receptors and Other Organellar Ca2+Channels (original) (raw)

2019, Cold Spring Harbor Perspectives in Biology

The pro-and antiapoptotic proteins belonging to the B-cell lymphoma-2 (Bcl-2) family exert a critical control over cell-death processes by enabling or counteracting mitochondrial outer membrane permeabilization. Beyond this mitochondrial function, several Bcl-2 family members have emerged as critical modulators of intracellular Ca 2+ homeostasis and dynamics, showing proapoptotic and antiapoptotic functions. Bcl-2 family proteins specifically target several intracellular Ca 2+-transport systems, including organellar Ca 2+ channels: inositol 1,4,5-trisphosphate receptors (IP 3 Rs) and ryanodine receptors (RyRs), Ca 2+-release channels mediating Ca 2+ flux from the endoplasmic reticulum, as well as voltage-dependent anion channels (VDACs), which mediate Ca 2+ flux across the mitochondrial outer membrane into the mitochondria. Although the formation of protein complexes between Bcl-2 proteins and these channels has been extensively studied, a major advance during recent years has been elucidating the complex interaction of Bcl-2 proteins with IP 3 Rs. Distinct interaction sites for different Bcl-2 family members were identified in the primary structure of IP 3 Rs. The unique molecular profiles of these Bcl-2 proteins may account for their distinct functional outcomes when bound to IP 3 Rs. Furthermore, Bcl-2 inhibitors used in cancer therapy may affect IP 3 R function as part of their proapoptotic effect and/or as an adverse effect in healthy cells. B-CELL LYMPHOMA-2 (Bcl-2) FAMILY OF PROTEINS T he Bcl-2 family of proteins consists of proand antiapoptotic members, which are characterized by the presence of at least one of the four highly conserved α-helical motifs, termed Bcl-2 homology (BH) domains (Adams and Cory 1998). The antiapoptotic family members, such as Bcl-2, Bcl-Xl, and Mcl-1, contain all four BH domains where the BH1, BH2, and BH3 domains form a hydrophobic cleft (Fig. 1A). The hydrophobic cleft is separated from the amino-terminal BH4 domain by an unstructured