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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).
DOI: https://doi.org/10.1073/pnas.0907555106
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.
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About
- Item ORO ID
- 34851
- Item Type
- Journal Item
- ISSN
- 1091-6490
- Academic Unit or School
-
Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM) - Copyright Holders
- © 2009 National Academy of Sciences
- Depositing User
- Martin Bootman