Biphasic Regulation of InsP3 Receptor Gating by Dual Ca2+ Release Channel BH3-like Domains Mediates Bcl-xL Control of Cell Viability

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2016 Mar 16

PMID 26976600

Citations 27

Authors

Jun Yang

Horia Vais

Wenen Gu

J Kevin Foskett

Affiliations

Soon will be listed here.

Abstract

Antiapoptotic Bcl-2 family members interact with inositol trisphosphate receptor (InsP3R) Ca(2+)release channels in the endoplasmic reticulum to modulate Ca(2+)signals that affect cell viability. However, the molecular details and consequences of their interactions are unclear. Here, we found that Bcl-xL activates single InsP3R channels with a biphasic concentration dependence. The Bcl-xLBcl-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 InsP3R that play critical roles in Ca(2+) signaling and cell viability.

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