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Selective regulation of IP3-receptor-mediated Ca2+ signaling and apoptosis by the BH4 domain of Bcl-2 versus Bcl-Xl

G Monaco, Elke Decrock UGent, H Akl, Raf Ponsaerts, T Vervliet, T Luyten, M De Maeyer, L Missiaen, CW Distelhorst and H De Smedt, et al. (2012) CELL DEATH AND DIFFERENTIATION. 19(2). p.295-309
abstract
Antiapoptotic B-cell lymphoma 2 (Bcl-2) targets the inositol 1,4,5-trisphosphate receptor (IP3R) via its BH4 domain, thereby suppressing IP3R Ca2+-flux properties and protecting against Ca2+-dependent apoptosis. Here, we directly compared IP3R inhibition by BH4-Bcl-2 and BH4-Bcl-Xl. In contrast to BH4-Bcl-2, BH4-Bcl-Xl neither bound the modulatory domain of IP3R nor inhibited IP3-induced Ca2+ 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 IP3R-binding and -inhibitory properties, whereas changing Asp11 into Lys in BH4-Bcl-Xl induced IP3R binding and inhibition. This difference in IP3R 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 IP3R-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 IP3R, 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 Ca2+-driven apoptosis by these functional domains. Mutating this residue affects the function of Bcl-2 in Ca2+ signaling and apoptosis.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
antiapoptotic Bcl-2-family members, apoptosis, calcium signaling, endoplasmic reticulum, intracellular Ca2+-release channels, ENDOPLASMIC-RETICULUM CA2+, MITOCHONDRIAL OUTER-MEMBRANE, INOSITOL 1, 4, 5-TRISPHOSPHATE RECEPTORS, CELL-DEATH, FAMILY-MEMBERS, TRISPHOSPHATE RECEPTOR, CALCIUM-RELEASE, ER, BAX, MODULATION
journal title
CELL DEATH AND DIFFERENTIATION
Cell Death Differ.
volume
19
issue
2
pages
295 - 309
Web of Science type
Article
Web of Science id
000299160600012
JCR category
BIOCHEMISTRY & MOLECULAR BIOLOGY
JCR impact factor
8.371 (2012)
JCR rank
26/288 (2012)
JCR quartile
1 (2012)
ISSN
1350-9047
DOI
10.1038/cdd.2011.97
language
English
UGent publication?
yes
classification
A1
copyright statement
I have retained and own the full copyright for this publication
id
2106375
handle
http://hdl.handle.net/1854/LU-2106375
date created
2012-05-14 20:50:01
date last changed
2012-05-15 09:21:49
@article{2106375,
  abstract     = {Antiapoptotic B-cell lymphoma 2 (Bcl-2) targets the inositol 1,4,5-trisphosphate receptor (IP3R) via its BH4 domain, thereby suppressing IP3R Ca2+-flux properties and protecting against Ca2+-dependent apoptosis. Here, we directly compared IP3R inhibition by BH4-Bcl-2 and BH4-Bcl-Xl. In contrast to BH4-Bcl-2, BH4-Bcl-Xl neither bound the modulatory domain of IP3R nor inhibited IP3-induced Ca2+ 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 IP3R-binding and -inhibitory properties, whereas changing Asp11 into Lys in BH4-Bcl-Xl induced IP3R binding and inhibition. This difference in IP3R 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 IP3R-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 IP3R, 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 Ca2+-driven apoptosis by these functional domains. Mutating this residue affects the function of Bcl-2 in Ca2+ signaling and apoptosis.},
  author       = {Monaco, G and Decrock, Elke and Akl, H and Ponsaerts, Raf and Vervliet, T and Luyten, T and De Maeyer, M and Missiaen, L and Distelhorst, CW and De Smedt, H and Parys, JB and Leybaert, Luc and Bultynck, Geert},
  issn         = {1350-9047},
  journal      = {CELL DEATH AND DIFFERENTIATION},
  keyword      = {antiapoptotic Bcl-2-family members,apoptosis,calcium signaling,endoplasmic reticulum,intracellular Ca2+-release channels,ENDOPLASMIC-RETICULUM CA2+,MITOCHONDRIAL OUTER-MEMBRANE,INOSITOL 1,4,5-TRISPHOSPHATE RECEPTORS,CELL-DEATH,FAMILY-MEMBERS,TRISPHOSPHATE RECEPTOR,CALCIUM-RELEASE,ER,BAX,MODULATION},
  language     = {eng},
  number       = {2},
  pages        = {295--309},
  title        = {Selective regulation of IP3-receptor-mediated Ca2+ signaling and apoptosis by the BH4 domain of Bcl-2 versus Bcl-Xl},
  url          = {http://dx.doi.org/10.1038/cdd.2011.97},
  volume       = {19},
  year         = {2012},
}

Chicago
Monaco, G, Elke Decrock, H Akl, Raf Ponsaerts, T Vervliet, T Luyten, M De Maeyer, et al. 2012. “Selective Regulation of IP3-receptor-mediated Ca2+ Signaling and Apoptosis by the BH4 Domain of Bcl-2 Versus Bcl-Xl.” Cell Death and Differentiation 19 (2): 295–309.
APA
Monaco, G., Decrock, E., Akl, H., Ponsaerts, R., Vervliet, T., Luyten, T., De Maeyer, M., et al. (2012). Selective regulation of IP3-receptor-mediated Ca2+ signaling and apoptosis by the BH4 domain of Bcl-2 versus Bcl-Xl. CELL DEATH AND DIFFERENTIATION, 19(2), 295–309.
Vancouver
1.
Monaco G, Decrock E, Akl H, Ponsaerts R, Vervliet T, Luyten T, et al. Selective regulation of IP3-receptor-mediated Ca2+ signaling and apoptosis by the BH4 domain of Bcl-2 versus Bcl-Xl. CELL DEATH AND DIFFERENTIATION. 2012;19(2):295–309.
MLA
Monaco, G, Elke Decrock, H Akl, et al. “Selective Regulation of IP3-receptor-mediated Ca2+ Signaling and Apoptosis by the BH4 Domain of Bcl-2 Versus Bcl-Xl.” CELL DEATH AND DIFFERENTIATION 19.2 (2012): 295–309. Print.