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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...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Portland Press Ltd.
2016
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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 |
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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 |
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