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Neutron reflectometry and NMR spectroscopy of full-length Bcl-2 protein reveal its membrane localization and conformation
B-cell lymphoma 2 (Bcl-2) proteins are the main regulators of mitochondrial apoptosis. Anti-apoptotic Bcl-2 proteins possess a hydrophobic tail-anchor enabling them to translocate to their target membrane and to shift into an active conformation where they inhibit pro-apoptotic Bcl-2 proteins to ens...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079415/ https://www.ncbi.nlm.nih.gov/pubmed/33907308 http://dx.doi.org/10.1038/s42003-021-02032-1 |
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author | Mushtaq, Ameeq Ul Ådén, Jörgen Clifton, Luke A. Wacklin-Knecht, Hanna Campana, Mario Dingeldein, Artur P. G. Persson, Cecilia Sparrman, Tobias Gröbner, Gerhard |
author_facet | Mushtaq, Ameeq Ul Ådén, Jörgen Clifton, Luke A. Wacklin-Knecht, Hanna Campana, Mario Dingeldein, Artur P. G. Persson, Cecilia Sparrman, Tobias Gröbner, Gerhard |
author_sort | Mushtaq, Ameeq Ul |
collection | PubMed |
description | B-cell lymphoma 2 (Bcl-2) proteins are the main regulators of mitochondrial apoptosis. Anti-apoptotic Bcl-2 proteins possess a hydrophobic tail-anchor enabling them to translocate to their target membrane and to shift into an active conformation where they inhibit pro-apoptotic Bcl-2 proteins to ensure cell survival. To address the unknown molecular basis of their cell-protecting functionality, we used intact human Bcl-2 protein natively residing at the mitochondrial outer membrane and applied neutron reflectometry and NMR spectroscopy. Here we show that the active full-length protein is entirely buried into its target membrane except for the regulatory flexible loop domain (FLD), which stretches into the aqueous exterior. The membrane location of Bcl-2 and its conformational state seems to be important for its cell-protecting activity, often infamously upregulated in cancers. Most likely, this situation enables the Bcl-2 protein to sequester pro-apoptotic Bcl-2 proteins at the membrane level while sensing cytosolic regulative signals via its FLD region. |
format | Online Article Text |
id | pubmed-8079415 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-80794152021-05-05 Neutron reflectometry and NMR spectroscopy of full-length Bcl-2 protein reveal its membrane localization and conformation Mushtaq, Ameeq Ul Ådén, Jörgen Clifton, Luke A. Wacklin-Knecht, Hanna Campana, Mario Dingeldein, Artur P. G. Persson, Cecilia Sparrman, Tobias Gröbner, Gerhard Commun Biol Article B-cell lymphoma 2 (Bcl-2) proteins are the main regulators of mitochondrial apoptosis. Anti-apoptotic Bcl-2 proteins possess a hydrophobic tail-anchor enabling them to translocate to their target membrane and to shift into an active conformation where they inhibit pro-apoptotic Bcl-2 proteins to ensure cell survival. To address the unknown molecular basis of their cell-protecting functionality, we used intact human Bcl-2 protein natively residing at the mitochondrial outer membrane and applied neutron reflectometry and NMR spectroscopy. Here we show that the active full-length protein is entirely buried into its target membrane except for the regulatory flexible loop domain (FLD), which stretches into the aqueous exterior. The membrane location of Bcl-2 and its conformational state seems to be important for its cell-protecting activity, often infamously upregulated in cancers. Most likely, this situation enables the Bcl-2 protein to sequester pro-apoptotic Bcl-2 proteins at the membrane level while sensing cytosolic regulative signals via its FLD region. Nature Publishing Group UK 2021-04-27 /pmc/articles/PMC8079415/ /pubmed/33907308 http://dx.doi.org/10.1038/s42003-021-02032-1 Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Mushtaq, Ameeq Ul Ådén, Jörgen Clifton, Luke A. Wacklin-Knecht, Hanna Campana, Mario Dingeldein, Artur P. G. Persson, Cecilia Sparrman, Tobias Gröbner, Gerhard Neutron reflectometry and NMR spectroscopy of full-length Bcl-2 protein reveal its membrane localization and conformation |
title | Neutron reflectometry and NMR spectroscopy of full-length Bcl-2 protein reveal its membrane localization and conformation |
title_full | Neutron reflectometry and NMR spectroscopy of full-length Bcl-2 protein reveal its membrane localization and conformation |
title_fullStr | Neutron reflectometry and NMR spectroscopy of full-length Bcl-2 protein reveal its membrane localization and conformation |
title_full_unstemmed | Neutron reflectometry and NMR spectroscopy of full-length Bcl-2 protein reveal its membrane localization and conformation |
title_short | Neutron reflectometry and NMR spectroscopy of full-length Bcl-2 protein reveal its membrane localization and conformation |
title_sort | neutron reflectometry and nmr spectroscopy of full-length bcl-2 protein reveal its membrane localization and conformation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079415/ https://www.ncbi.nlm.nih.gov/pubmed/33907308 http://dx.doi.org/10.1038/s42003-021-02032-1 |
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