The BH4 domain of Bcl-2 inhibits ER calcium release and apoptosis by binding the regulatory and coupling domain of the IP3 receptor.
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.
Rong
Yi-Ping
YP
Departments of Medicine and Pharmacology, Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA.
Bultynck
Geert
G
Aromolaran
Ademuyiwa S
AS
Zhong
Fei
F
Parys
Jan B
JB
De Smedt
Humbert
H
Mignery
Gregory A
GA
Roderick
H Llewelyn
HL
Bootman
Martin D
MD
Distelhorst
Clark W
CW
D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001665:Binding Sites; D015153:Blotting, Western; D017252:CD3 Complex / Q000276:immunology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism*; D019169:Jurkat Cells; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*
D000906:Antibodies; D017252:CD3 Complex; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009842:Oligopeptides; D019253:Proto-Oncogene Proteins c-bcl-2; D002118:Calcium
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