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The selective BH4-domain biology of Bcl-2-family members: IP3Rs and beyond

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Abstract

Anti-apoptotic Bcl-2-family members not only neutralize pro-apoptotic proteins but also directly regulate intracellular Ca2+ signaling from the endoplasmic reticulum (ER), critically controlling cellular health, survival, and death initiation. Furthermore, distinct Bcl-2-family members may selectively regulate inositol 1,4,5-trisphosphate receptor (IP3R): Bcl-2 likely acts as an endogenous inhibitor of the IP3R, preventing pro-apoptotic Ca2+ transients, while Bcl-XL likely acts as an endogenous IP3R-sensitizing protein promoting pro-survival Ca2+ oscillations. Furthermore, distinct functional domains in Bcl-2 and Bcl-XL may underlie the divergence in IP3R regulation. The Bcl-2 homology (BH) 4 domain, which targets the central modulatory domain of the IP3R, is likely to be Bcl-2’s determining factor. In contrast, the hydrophobic cleft targets the C-terminal Ca2+-channel tail and might be more crucial for Bcl-XL’s function. Furthermore, one amino acid critically different in the sequence of Bcl-2’s and Bcl-XL’s BH4 domains underpins their selective effect on Ca2+ signaling and distinct biological properties of Bcl-2 versus Bcl-XL. This difference is evolutionary conserved across five classes of vertebrates and may represent a fundamental divergence in their biological function. Moreover, these insights open novel avenues to selectively suppress malignant Bcl-2 function in cancer cells by targeting its BH4 domain, while maintaining essential Bcl-XL functions in normal cells. Thus, IP3R-derived molecules that mimic the BH4 domain’s binding site on the IP3R may function synergistically with BH3-mimetic molecules selectivity suppressing Bcl-2’s proto-oncogenic activity. Finally, a more general role for the BH4 domain on IP3Rs, rather than solely anti-apoptotic, may not be excluded as part of a complex network of molecular interactions.

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Acknowledgments

Work in the author’s laboratory has been supported by research grants from the Research Council of the KU Leuven (OT/STRT1/10/044), from the Research Foundation—Flanders (FWO) grants G.0788.11 and G.0571.12, and from the Royal Flemish Academy of Belgium for Science and the Arts (Research Award from the Octaaf Dupont Foundation 2010).

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Authors and Affiliations

  1. Laboratory of Molecular and Cellular Signaling, Department Cellular and Molecular Medicine, KU Leuven, Campus Gasthuisberg O/N-1 bus 802, 3000, Leuven, Belgium

    Giovanni Monaco, Tim Vervliet, Haidar Akl & Geert Bultynck

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  1. Giovanni Monaco
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  2. Tim Vervliet
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  3. Haidar Akl
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  4. Geert Bultynck
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Correspondence to Geert Bultynck.

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G. Monaco, T. Vervliet and H. Akl contributed equally to this work.

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Monaco, G., Vervliet, T., Akl, H. et al. The selective BH4-domain biology of Bcl-2-family members: IP3Rs and beyond. Cell. Mol. Life Sci. 70, 1171–1183 (2013). https://doi.org/10.1007/s00018-012-1118-y

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  • DOI: https://doi.org/10.1007/s00018-012-1118-y

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