Rong, Yi-Ping; Bultynck, Geert; Aromolaran, Ademuyiwa S.; Zhong, Fei; Parys, Jan B.; De Smedt, Humbert; Mignery, Gregory A.; Roderick, H Llewelyn; Bootman, Martin and Distelhorst, Clark W.
(2009).
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| DOI (Digital Object Identifier) Link: | https://doi.org/10.1073/pnas.0907555106 |
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| Google Scholar: | Look up in Google Scholar |
Abstract
Although the presence of a BH4 domain distinguishes the antiapoptotic protein Bcl-2 from its proapoptotic relatives, little is known about its function. BH4 deletion converts Bcl-2 into a proapoptotic protein, whereas a TAT-BH4 fusion peptide inhibits apoptosis and improves survival in models of disease due to accelerated apoptosis. Thus, the BH4 domain has antiapoptotic activity independent of full-length Bcl-2. Here we report that the BH4 domain mediates interaction of Bcl-2 with the inositol 1,4,5-trisphosphate (IP3) receptor, an IP3-gated Ca(2+) channel on the endoplasmic reticulum (ER). BH4 peptide binds to the regulatory and coupling domain of the IP3 receptor and inhibits IP3-dependent channel opening, Ca(2+) release from the ER, and Ca(2+)-mediated apoptosis. A peptide inhibitor of Bcl-2-IP3 receptor interaction prevents these BH4-mediated effects. By inhibiting proapoptotic Ca(2+) signals at their point of origin, the Bcl-2 BH4 domain has the facility to block diverse pathways through which Ca(2+) induces apoptosis.
| Item Type: | Journal Item |
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| Copyright Holders: | 2009 National Academy of Sciences |
| ISSN: | 1091-6490 |
| Academic Unit/School: | Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences Faculty of Science, Technology, Engineering and Mathematics (STEM) |
| Interdisciplinary Research Centre: | Biomedical Research Network (BRN) Health and Wellbeing PRA (Priority Research Area) |
| Item ID: | 34851 |
| Depositing User: | Martin Bootman |
| Date Deposited: | 25 Oct 2012 10:02 |
| Last Modified: | 11 Sep 2017 15:32 |
| URI: | http://oro.open.ac.uk/id/eprint/34851 |
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