Allosteric Cross-Talk between the Hydrophobic Cleft and the BH4 Domain of Bcl-2 in Control of IP3R Activity

Bcl-2 is an important regulator of inositol 1,4,5-trisphosphate receptor (IP3R) activity and, thus of Ca2+ release from internal stores and associated processes, including cellular proliferation and death. The presence of multiple regulatory domains in both proteins suggests a complex interaction. Earlier reports have shown the involvement of both the BH4 and the transmembrane domains of Bcl-2 in regulating IP3R activity, while the Bcl-2 hydrophobic cleft was associated primarily with its anti-apoptotic, IP3R-independent, action at the mitochondria. Here, we show that occlusion of Bcl-2’s hydrophobic cleft by the drug ABT-199 finely modulates IP3R gating in the low open probability regime, characteristic of the basal IP3R activity in non-excited cells. Complementary MD simulations allowed us to propose a model of this modulation, involving an allosteric interaction with the BH4 domain on the opposite side of Bcl-2.