Bcl-2 and IP3 compete for the ligand-binding domain of IP3Rs modulating Ca2+ signaling output.

Bcl-2 and IP3 compete for the ligand-binding domain of IP3Rs modulating Ca2+ signaling output.
Cell Mol Life Sci. 2019 Apr 16;:
Authors: Ivanova H, Wagner LE, Tanimura A, Vandermarliere E, Luyten T, Welkenhuyzen K, Alzayady KJ, Wang L, Hamada K, Mikoshiba K, De Smedt H, Martens L, Yule DI, Parys JB, Bultynck G
Abstract
Bcl-2 proteins have emerged as critical regulators of intracellular Ca2+ dynamics by directly targeting and inhibiting the IP3 receptor (IP3R), a major intracellular Ca2+-release channel. Here, we demonstrate that such inhibition occurs under conditions of basal, but not high IP3R activity, since overexpressed and purified Bcl-2 (or its BH4 domain) can inhibit IP3R function provoked by low concentration of agonist or IP3, while fails to attenuate against high concentration of agonist or IP3. Surprisingly, Bcl-2 remained capable of inhibiting IP3R1 channels lacking the residues encompassing the previously identified Bcl-2-binding site (a.a. 1380-1408) located in the ARM2 domain, part of the modulatory region. Using a plethora of computational, biochemical and biophysical methods, we demonstrate that Bcl-2 and more particularly its BH4 domain bind to the ligand-binding domain (LBD) of IP3R1. In line with this finding, the interaction between the LBD and Bcl-2 (or its BH4 domain) was sensitive to IP3 and adenophostin A, ligands of the IP3R. Vice versa, the BH4 domain of Bcl-2 counteracted the binding of IP3 to the LBD. C...

Source: Cellular and Molecular Life Sciences : CMLS - April 15, 2019 Category: Cytology Authors: Ivanova H, Wagner LE, Tanimura A, Vandermarliere E, Luyten T, Welkenhuyzen K, Alzayady KJ, Wang L, Hamada K, Mikoshiba K, De Smedt H, Martens L, Yule DI, Parys JB, Bultynck G Tags: Cell Mol Life Sci Source Type: research