Ion Channel Activity of the BH3 Only Bcl-2 Family Member, BID

Sharon L Schendel,Rustam Azimov,Krzysztof Pawłowski,Adam Godzik,Bruce L Kagan,John C Reed

doi:10.1074/jbc.274.31.21932

Sharon L Schendel, Rustam Azimov + Show 4 more

Open Access

https://doi.org/10.1074/jbc.274.31.21932

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Abstract

BID is a member of the BH3-only subgroup of Bcl-2 family proteins that displays pro-apoptotic activity. The NH(2)-terminal region of BID contains a caspase-8 (Casp-8) cleavage site and the cleaved form of BID translocates to mitochondrial membranes where it is a potent inducer of cytochrome c release. Secondary structure and fold predictions suggest that BID has a high degree of alpha-helical content and structural similarity to Bcl-X(L), which itself is highly similar to bacterial pore-forming toxins. Moreover, circular dichroism analysis confirmed a high alpha-helical content of BID. Amino-terminal truncated BIDDelta1-55, mimicking the Casp-8-cleaved molecule, formed channels in planar bilayers at neutral pH and in liposomes at acidic pH. In contrast, full-length BID displayed channel activity only at nonphysiological pH 4.0 (but not at neutral pH) in planar bilayers and failed to form channels in liposomes even under acidic conditions. On a single channel level, BIDDelta1-55 channels were voltage-gated and exhibited multiconductance behavior at neutral pH. When full-length BID was cleaved by Casp-8, it too demonstrated channel activity similar to that seen with BIDDelta1-55. Thus, BID appears to share structural and functional similarity with other Bcl-2 family proteins known to have channel-forming activity, but its activity exhibits a novel form of activation: proteolytic cleavage.

Highlights

Bcl-2 protein family members play an important role in governing a cell’s decision to heed or disregard signals to enter pathways for programmed cell death and apoptosis
Escape of cytochrome c (Cyt c) from mitochondria represents a critical event in initiating the caspase activation cascade, through its interaction with Apaf-1, which induces processing and activation of the cell death protease caspase-9 (Casp-9) [11, 12]
The portal through which Cyt c passes into the cytoplasm is unknown, Bax and the mitochondrial permeability pore complex appear to play important roles in Cyt c release [13, 14]

Summary

Introduction

Bcl-2 protein family members play an important role in governing a cell’s decision to heed or disregard signals to enter pathways for programmed cell death and apoptosis. Amino-terminal truncated BID⌬1–55, mimicking the Casp-8-cleaved molecule, formed channels in planar bilayers at neutral pH and in liposomes at acidic pH.

Results

Conclusion