• Yi-Ping Rong, Geert Bultynck, Ademuyiwa S Aromolaran, Fei Zhong, Jan B Parys, Humbert De Smedt, Gregory A Mignery, H Llewelyn Roderick, Martin D Bootman, and Clark W Distelhorst.
• Departments of Medicine and Pharmacology, Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA.
• Proc. Natl. Acad. Sci. U.S.A. 2009 Aug 25; 106 (34): 14397-402.

AbstractAlthough 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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