RRC ID 57756
Author Ivanova H, Wagner LE 2nd, 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.
Title Bcl-2 and IP3 compete for the ligand-binding domain of IP3Rs modulating Ca2+ signaling output.
Journal Cell Mol Life Sci
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. Collectively, our work reveals a novel mechanism by which Bcl-2 influences IP3R activity at the level of the LBD. This allows for exquisite modulation of Bcl-2's inhibitory properties on IP3Rs that is tunable to the level of IP3 signaling in cells.
Volume 76(19)
Pages 3843-3859
Published 2019-10-1
DOI 10.1007/s00018-019-03091-8
PII 10.1007/s00018-019-03091-8
PMID 30989245
MeSH Adenosine / analogs & derivatives Adenosine / metabolism Amino Acid Sequence Animals Binding, Competitive COS Cells Calcium Signaling* Cells, Cultured Chlorocebus aethiops Inositol 1,4,5-Trisphosphate / metabolism* Inositol 1,4,5-Trisphosphate Receptors / agonists Inositol 1,4,5-Trisphosphate Receptors / antagonists & inhibitors* Inositol 1,4,5-Trisphosphate Receptors / chemistry Inositol 1,4,5-Trisphosphate Receptors / genetics Ligands Mice Molecular Docking Simulation Protein Domains Proto-Oncogene Proteins c-bcl-2 / chemistry Proto-Oncogene Proteins c-bcl-2 / metabolism* Sequence Deletion
IF 6.496
Times Cited 5
Human and Animal Cells COS-7(RCB0539)