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.
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|DOI (Digital Object Identifier) Link:||http://dx.doi.org/doi:10.1073/pnas.0907555106|
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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 Article|
|Copyright Holders:||2009 National Academy of Sciences|
|Academic Unit/Department:||Science > Life, Health and Chemical Sciences|
|Depositing User:||Martin Bootman|
|Date Deposited:||25 Oct 2012 10:02|
|Last Modified:||25 Oct 2012 10:02|
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