Intrinsic Instability of BOK Enables Membrane Permeabilization in Apoptosis

Cell Reports
Janet H ZhengTudor Moldoveanu

Abstract

The effector B cell lymphoma-2 (BCL-2) protein BCL-2 ovarian killer (BOK) induces mitochondrial outer membrane permeabilization (MOMP) to initiate apoptosis upon inhibition of the proteasome. How BOK mediates MOMP is mechanistically unknown. The NMR structure of the BCL-2 core of human BOK reveals a conserved architecture with an atypical hydrophobic groove that undergoes conformational exchange. Remarkably, the BCL-2 core of BOK spontaneously associates with purified mitochondria to release cytochrome c in MOMP assays. Alanine substitution of a unique glycine in helix α1 stabilizes BOK, as shown by thermal shift and urea denaturation analyses, and significantly inhibits MOMP, liposome permeabilization, and cell death. Activated BID does not activate WT BOK or the stabilized alanine mutant to promote cell death. We propose that BOK-mediated membrane permeabilization is governed in part by its unique metastability of the hydrophobic groove and helix α1 and not through activation by BH3 ligands.

Citations

Oct 23, 2019·Nature Reviews. Molecular Cell Biology·Florian J Bock, Stephen W G Tait
Oct 2, 2019·Cold Spring Harbor Perspectives in Biology·Tudor Moldoveanu, Peter E Czabotar
Aug 21, 2018·Oncotarget·Tudor Moldoveanu, Janet H Zheng
Dec 14, 2018·Frontiers in Oncology·Anne Slomp, Victor Peperzak
Apr 13, 2019·Cell Death and Differentiation·Jacqualyn J SchulmanRichard J H Wojcikiewicz
Apr 27, 2020·Apoptosis : an International Journal on Programmed Cell Death·Prashanthi Ramesh, Jan Paul Medema
Jan 17, 2020·Biomolecules·Suresh BanjaraMarc Kvansakul
Oct 13, 2020·Frontiers in Cell and Developmental Biology·Samara Naim, Thomas Kaufmann
Feb 9, 2021·Frontiers in Cell and Developmental Biology·Qian LiWeijun Fu
Dec 10, 2020·Biomolecules·Raed ShalabyAna J García-Sáez
Oct 15, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Ruiting ShanBin Liu
Mar 28, 2021·Biochemical and Biophysical Research Communications·Laura M SzczesniakRichard J H Wojcikiewicz
May 4, 2021·Journal of Medicinal Chemistry·Justin P PogmoreDavid W Andrews

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Datasets Mentioned

BETA
304023

Methods Mentioned

BETA
nuclear magnetic resonance
NMR
thermal shift
transfection
fluorescence-activated cell sorting
conformational exchange
electrophoresis
gel filtration
Protein Thermal Shift
PCR

Software Mentioned

GraphPad
Excel
MOLMOL
Pymol
GraphPad Prism
FlowJo
HHpred
BOK
UNIO
PROCHECK

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