期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 13, 页码 E1953-E1962出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1517935113
关键词
Bcl-2; ion channel; calcium; apoptosis; mitochondria
资金
- National Institutes of Health [GM56328]
- Shanghai Institute of Planned Parenthood Research Grant [PD2012-4]
Antiapoptotic Bcl-2 family members interact with inositol trisphosphate receptor (InsP(3)R) Ca2+ release channels in the endoplasmic reticulum to modulate Ca2+ signals that affect cell viability. However, the molecular details and consequences of their interactions are unclear. Here, we found that Bcl-xL activates single InsP(3)R channels with a biphasic concentration dependence. The Bcl-xL Bcl-2 homology 3 (BH3) domain-binding pocket mediates both high-affinity channel activation and low-affinity inhibition. Bcl-xL activates channel gating by binding to two BH3 domain-like helices in the channel carboxyl terminus, whereas inhibition requires binding to one of them and to a previously identified Bcl-2 interaction site in the channel-coupling domain. Disruption of these interactions diminishes cell viability and sensitizes cells to apoptotic stimuli. Our results identify BH3-like domains in an ion channel and they provide a unifying model of the effects of antiapoptotic Bcl-2 proteins on the InsP(3)R that play critical roles in Ca2+ signaling and cell viability.
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