The trans-membrane domain of Bcl-2α, but not its hydrophobic cleft, is a critical determinant for efficient IP3 receptor inhibition
| Autor: | Giovanni Monaco, Geert Bultynck, Kirsten Welkenhuyzen, Larry E. Wagner, Humbert De Smedt, Tomas Luyten, David I. Yule, Hristina Ivanova, Natalia Prevarskaya, Bruno Seitaj, Jan B. Parys, George Shapovalov, Abigael Ritaine |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Protein domain IP3 receptor Apoptosis hydrophobic cleft calcium signaling 03 medical and health sciences 0302 clinical medicine Protein Domains medicine Humans Inositol 1 4 5-Trisphosphate Receptors Binding site Calcium signaling Sulfonamides Chemistry Inositol trisphosphate receptor Bridged Bicyclo Compounds Heterocyclic Cell biology 030104 developmental biology Proto-Oncogene Proteins c-bcl-2 Oncology Mechanism of action 030220 oncology & carcinogenesis Cancer cell trans-membrane domain Calcium medicine.symptom anti-apoptotic Bcl-2 Hydrophobic and Hydrophilic Interactions Function (biology) Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.11005 |
| Popis: | The anti-apoptotic Bcl-2 protein is emerging as an efficient inhibitor of IP3R function, contributing to its oncogenic properties. Yet, the underlying molecular mechanisms remain not fully understood. Using mutations or pharmacological inhibition to antagonize Bcl-2’s hydrophobic cleft, we excluded this functional domain as responsible for Bcl-2-mediated IP3Rs inhibition. In contrast, the deletion of the C-terminus, containing the trans-membrane domain, which is only present in Bcl-2a, but not in Bcl-2β, led to impaired inhibition of IP3R-mediated Ca2+ release and staurosporine-induced apoptosis. Strikingly, the trans-membrane domain was sufficient for IP3R binding and inhibition. We therefore propose a novel model, in which the Bcl-2’s C-terminus serves as a functional anchor, which beyond mere ER-membrane targeting, underlies efficient IP3R inhibition by (i) positioning the BH4 domain in the close proximity of its binding site on IP3R, thus facilitating their interaction; (ii) inhibiting IP3R-channel openings through a direct interaction with the C-terminal region of the channel downstream of the channel-pore. Finally, since the hydrophobic cleft of Bcl-2 was not involved in IP3R suppression, our findings indicate that ABT-199 does not interfere with IP3R regulation by Bcl-2 and its mechanism of action as a cell-death therapeutic in cancer cells likely does not involve Ca2+ signaling. ispartof: Oncotarget vol:7 issue:34 pages:55704-55720 ispartof: location:United States status: published |
| Databáze: | OpenAIRE |
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