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Title: Selective regulation of IP(3)-receptor-mediated Ca(2+) signaling and apoptosis by the BH4 domain of Bcl-2 versus Bcl-Xl
Authors: Monaco, Giovanni
Decrock, E
Akl, Haidar
Ponsaerts, Raf
Vervliet, Tim
Luyten, Tomas
De Maeyer, Marc
Missiaen, Ludwig
Distelhorst, C W
De Smedt, Humbert
Parys, Jan
Leybaert, L
Bultynck, Geert # ×
Issue Date: Feb-2012
Publisher: E. Arnold
Series Title: Cell Death and Differentiation vol:19 issue:2 pages:295-309
Article number: 10.1038/cdd.2011.97
Abstract: Antiapoptotic B-cell lymphoma 2 (Bcl-2) targets the inositol 1,4,5-trisphosphate receptor (IP(3)R) via its BH4 domain, thereby suppressing IP(3)R Ca(2+)-flux properties and protecting against Ca(2+)-dependent apoptosis. Here, we directly compared IP(3)R inhibition by BH4-Bcl-2 and BH4-Bcl-Xl. In contrast to BH4-Bcl-2, BH4-Bcl-Xl neither bound the modulatory domain of IP(3)R nor inhibited IP(3)-induced Ca(2+) release (IICR) in permeabilized and intact cells. We identified a critical residue in BH4-Bcl-2 (Lys17) not conserved in BH4-Bcl-Xl (Asp11). Changing Lys17 into Asp in BH4-Bcl-2 completely abolished its IP(3)R-binding and -inhibitory properties, whereas changing Asp11 into Lys in BH4-Bcl-Xl induced IP(3)R binding and inhibition. This difference in IP(3)R regulation between BH4-Bcl-2 and BH4-Bcl-Xl controls their antiapoptotic action. Although both BH4-Bcl-2 and BH4-Bcl-Xl had antiapoptotic activity, BH4-Bcl-2 was more potent than BH4-Bcl-Xl. The effect of BH4-Bcl-2, but not of BH4-Bcl-Xl, depended on its binding to IP(3)Rs. In agreement with the IP(3)R-binding properties, the antiapoptotic activity of BH4-Bcl-2 and BH4-Bcl-Xl was modulated by the Lys/Asp substitutions. Changing Lys17 into Asp in full-length Bcl-2 significantly decreased its binding to the IP(3)R, its ability to inhibit IICR and its protection against apoptotic stimuli. A single amino-acid difference between BH4-Bcl-2 and BH4-Bcl-Xl therefore underlies differential regulation of IP(3)Rs and Ca(2+)-driven apoptosis by these functional domains. Mutating this residue affects the function of Bcl-2 in Ca(2+) signaling and apoptosis.Cell Death and Differentiation advance online publication, 5 August 2011; doi:10.1038/cdd.2011.97.
URI: 
ISSN: 1350-9047
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Molecular and Cellular Signaling
Biochemistry, Molecular and Structural Biology Section
× corresponding author
# (joint) last author

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