Cargando…

Small molecules reveal an alternative mechanism of Bax activation

The pro-apoptotic protein Bax commits a cell to death by permeabilizing the mitochondrial outer membrane (MOM). To obtain small-molecule probes for elucidating the molecular mechanism(s) of Bax activation, we screened for compounds that induced Bax-mediated liposome permeabilization. We identified f...

Descripción completa

Detalles Bibliográficos
Autores principales: Brahmbhatt, Hetal, Uehling, David, Al-awar, Rima, Leber, Brian, Andrews, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4847155/
https://www.ncbi.nlm.nih.gov/pubmed/26916338
http://dx.doi.org/10.1042/BCJ20160118
_version_ 1782429155396157440
author Brahmbhatt, Hetal
Uehling, David
Al-awar, Rima
Leber, Brian
Andrews, David
author_facet Brahmbhatt, Hetal
Uehling, David
Al-awar, Rima
Leber, Brian
Andrews, David
author_sort Brahmbhatt, Hetal
collection PubMed
description The pro-apoptotic protein Bax commits a cell to death by permeabilizing the mitochondrial outer membrane (MOM). To obtain small-molecule probes for elucidating the molecular mechanism(s) of Bax activation, we screened for compounds that induced Bax-mediated liposome permeabilization. We identified five structurally different small molecules that promoted both Bax targeting to and oligomerization at membranes. All five compounds initiated Bax oligomerization in the absence of membranes by a mechanism unlike Bax activation by Bcl-2 homology 3 domain (BH3) proteins. Some of the compounds induced Bax/Bak-dependent apoptosis in cells. Activation of Bax by the most active compound was poorly inhibited by the anti-apoptotic protein Bcl-XL and requires a cysteine residue at position 126 of Bax that is not required for activation by BH3 proteins. Our results reveal a novel pathway for Bax activation independent of pro-apoptotic BH3 proteins that may have important implications for the regulation of Bax activity in cells.
format Online
Article
Text
id pubmed-4847155
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Portland Press Ltd.
record_format MEDLINE/PubMed
spelling pubmed-48471552016-05-09 Small molecules reveal an alternative mechanism of Bax activation Brahmbhatt, Hetal Uehling, David Al-awar, Rima Leber, Brian Andrews, David Biochem J Research Articles The pro-apoptotic protein Bax commits a cell to death by permeabilizing the mitochondrial outer membrane (MOM). To obtain small-molecule probes for elucidating the molecular mechanism(s) of Bax activation, we screened for compounds that induced Bax-mediated liposome permeabilization. We identified five structurally different small molecules that promoted both Bax targeting to and oligomerization at membranes. All five compounds initiated Bax oligomerization in the absence of membranes by a mechanism unlike Bax activation by Bcl-2 homology 3 domain (BH3) proteins. Some of the compounds induced Bax/Bak-dependent apoptosis in cells. Activation of Bax by the most active compound was poorly inhibited by the anti-apoptotic protein Bcl-XL and requires a cysteine residue at position 126 of Bax that is not required for activation by BH3 proteins. Our results reveal a novel pathway for Bax activation independent of pro-apoptotic BH3 proteins that may have important implications for the regulation of Bax activity in cells. Portland Press Ltd. 2016-04-08 2016-04-15 /pmc/articles/PMC4847155/ /pubmed/26916338 http://dx.doi.org/10.1042/BCJ20160118 Text en © 2016 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY-NC-ND) (http://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Research Articles
Brahmbhatt, Hetal
Uehling, David
Al-awar, Rima
Leber, Brian
Andrews, David
Small molecules reveal an alternative mechanism of Bax activation
title Small molecules reveal an alternative mechanism of Bax activation
title_full Small molecules reveal an alternative mechanism of Bax activation
title_fullStr Small molecules reveal an alternative mechanism of Bax activation
title_full_unstemmed Small molecules reveal an alternative mechanism of Bax activation
title_short Small molecules reveal an alternative mechanism of Bax activation
title_sort small molecules reveal an alternative mechanism of bax activation
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4847155/
https://www.ncbi.nlm.nih.gov/pubmed/26916338
http://dx.doi.org/10.1042/BCJ20160118
work_keys_str_mv AT brahmbhatthetal smallmoleculesrevealanalternativemechanismofbaxactivation
AT uehlingdavid smallmoleculesrevealanalternativemechanismofbaxactivation
AT alawarrima smallmoleculesrevealanalternativemechanismofbaxactivation
AT leberbrian smallmoleculesrevealanalternativemechanismofbaxactivation
AT andrewsdavid smallmoleculesrevealanalternativemechanismofbaxactivation