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Anti-apoptotic BCL-2 regulation by changes in dynamics of its long unstructured loop
BCL-2, a key protein in inhibiting apoptosis, has a 65-residue-long highly flexible loop domain (FLD) located on the opposite side of its ligand-binding groove. In vivo phosphorylation of the FLD enhances the affinity of BCL-2 for pro-apoptotic ligands, and consequently anti-apoptotic activity. Howe...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665024/ https://www.ncbi.nlm.nih.gov/pubmed/33184407 http://dx.doi.org/10.1038/s42003-020-01390-6 |
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author | Lan, Yu-Jing Yeh, Pei-Shan Kao, Te-Yu Lo, Yuan-Chao Sue, Shih-Che Chen, Yu-Wen Hwang, Dennis W. Chiang, Yun-Wei |
author_facet | Lan, Yu-Jing Yeh, Pei-Shan Kao, Te-Yu Lo, Yuan-Chao Sue, Shih-Che Chen, Yu-Wen Hwang, Dennis W. Chiang, Yun-Wei |
author_sort | Lan, Yu-Jing |
collection | PubMed |
description | BCL-2, a key protein in inhibiting apoptosis, has a 65-residue-long highly flexible loop domain (FLD) located on the opposite side of its ligand-binding groove. In vivo phosphorylation of the FLD enhances the affinity of BCL-2 for pro-apoptotic ligands, and consequently anti-apoptotic activity. However, it remains unknown as to how the faraway, unstructured FLD modulates the affinity. Here we investigate the protein-ligand interactions by fluorescence techniques and monitor protein dynamics by DEER and NMR spectroscopy tools. We show that phosphomimetic mutations on the FLD lead to a reduction in structural flexibility, hence promoting ligand access to the groove. The bound pro-apoptotic ligands can be displaced by the BCL-2-selective inhibitor ABT-199 efficiently, and thus released to trigger apoptosis. We show that changes in structural flexibility on an unstructured loop can activate an allosteric protein that is otherwise structurally inactive. |
format | Online Article Text |
id | pubmed-7665024 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-76650242020-11-17 Anti-apoptotic BCL-2 regulation by changes in dynamics of its long unstructured loop Lan, Yu-Jing Yeh, Pei-Shan Kao, Te-Yu Lo, Yuan-Chao Sue, Shih-Che Chen, Yu-Wen Hwang, Dennis W. Chiang, Yun-Wei Commun Biol Article BCL-2, a key protein in inhibiting apoptosis, has a 65-residue-long highly flexible loop domain (FLD) located on the opposite side of its ligand-binding groove. In vivo phosphorylation of the FLD enhances the affinity of BCL-2 for pro-apoptotic ligands, and consequently anti-apoptotic activity. However, it remains unknown as to how the faraway, unstructured FLD modulates the affinity. Here we investigate the protein-ligand interactions by fluorescence techniques and monitor protein dynamics by DEER and NMR spectroscopy tools. We show that phosphomimetic mutations on the FLD lead to a reduction in structural flexibility, hence promoting ligand access to the groove. The bound pro-apoptotic ligands can be displaced by the BCL-2-selective inhibitor ABT-199 efficiently, and thus released to trigger apoptosis. We show that changes in structural flexibility on an unstructured loop can activate an allosteric protein that is otherwise structurally inactive. Nature Publishing Group UK 2020-11-12 /pmc/articles/PMC7665024/ /pubmed/33184407 http://dx.doi.org/10.1038/s42003-020-01390-6 Text en © The Author(s) 2020 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/. |
spellingShingle | Article Lan, Yu-Jing Yeh, Pei-Shan Kao, Te-Yu Lo, Yuan-Chao Sue, Shih-Che Chen, Yu-Wen Hwang, Dennis W. Chiang, Yun-Wei Anti-apoptotic BCL-2 regulation by changes in dynamics of its long unstructured loop |
title | Anti-apoptotic BCL-2 regulation by changes in dynamics of its long unstructured loop |
title_full | Anti-apoptotic BCL-2 regulation by changes in dynamics of its long unstructured loop |
title_fullStr | Anti-apoptotic BCL-2 regulation by changes in dynamics of its long unstructured loop |
title_full_unstemmed | Anti-apoptotic BCL-2 regulation by changes in dynamics of its long unstructured loop |
title_short | Anti-apoptotic BCL-2 regulation by changes in dynamics of its long unstructured loop |
title_sort | anti-apoptotic bcl-2 regulation by changes in dynamics of its long unstructured loop |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665024/ https://www.ncbi.nlm.nih.gov/pubmed/33184407 http://dx.doi.org/10.1038/s42003-020-01390-6 |
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