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Structural basis of the specificity and interaction mechanism of Bmf binding to pro-survival Bcl-2 family proteins
The apoptotic pathway is regulated by protein-protein interactions between members of the Bcl-2 family. Pro-survival Bcl-2 family proteins act as cell guardians and protect cells against death. Selective binding and neutralization of BH3-only proteins with pro-survival Bcl-2 family proteins is criti...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Research Network of Computational and Structural Biotechnology
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10407628/ https://www.ncbi.nlm.nih.gov/pubmed/37560128 http://dx.doi.org/10.1016/j.csbj.2023.07.017 |
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author | Wang, Haolan Guo, Ming Wei, Hudie Chen, Yongheng |
author_facet | Wang, Haolan Guo, Ming Wei, Hudie Chen, Yongheng |
author_sort | Wang, Haolan |
collection | PubMed |
description | The apoptotic pathway is regulated by protein-protein interactions between members of the Bcl-2 family. Pro-survival Bcl-2 family proteins act as cell guardians and protect cells against death. Selective binding and neutralization of BH3-only proteins with pro-survival Bcl-2 family proteins is critical for initiating apoptosis. In this study, the binding assay shows that the BH3 peptide derived from the BH3-only protein Bmf has a high affinity for the pro-survival proteins Bcl-2 and Bcl-xL, but a much lower affinity for Mcl-1. The complex structures of Bmf BH3 with Bcl-2, Bcl-xL and Mcl-1 reveal that the α-helical Bmf BH3 accommodates into the canonical groove of these pro-survival proteins, but the conformational changes and some interactions are different among the three complexes. Bmf BH3 forms conserved hydrophobic and salt bridge interactions with Bcl-2 and Bcl-xL, and also establishes several hydrogen bonds to support their binding. However, the highly conserved Asp-Arg salt bridge is not formed in the Mcl-1/Bmf BH3 complex, and few hydrogen bonds are observed. Furthermore, mutational analysis shows that substitutions of less-conserved residues in the α2-α3 region of these pro-survival Bcl-2 family proteins, as well as the highly conserved Arg, lead to significant changes in their binding affinity to Bmf BH3, while substitutions of less-conserved residues in Bmf BH3 have a more dramatic effect on its affinity to Mcl-1. This study provides structural insight into the specificity and interaction mechanism of Bmf BH3 binding to pro-survival Bcl-2 family proteins, and helps guide the design of BH3 mimics targeting pro-survival Bcl-2 family proteins. |
format | Online Article Text |
id | pubmed-10407628 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Research Network of Computational and Structural Biotechnology |
record_format | MEDLINE/PubMed |
spelling | pubmed-104076282023-08-09 Structural basis of the specificity and interaction mechanism of Bmf binding to pro-survival Bcl-2 family proteins Wang, Haolan Guo, Ming Wei, Hudie Chen, Yongheng Comput Struct Biotechnol J Research Article The apoptotic pathway is regulated by protein-protein interactions between members of the Bcl-2 family. Pro-survival Bcl-2 family proteins act as cell guardians and protect cells against death. Selective binding and neutralization of BH3-only proteins with pro-survival Bcl-2 family proteins is critical for initiating apoptosis. In this study, the binding assay shows that the BH3 peptide derived from the BH3-only protein Bmf has a high affinity for the pro-survival proteins Bcl-2 and Bcl-xL, but a much lower affinity for Mcl-1. The complex structures of Bmf BH3 with Bcl-2, Bcl-xL and Mcl-1 reveal that the α-helical Bmf BH3 accommodates into the canonical groove of these pro-survival proteins, but the conformational changes and some interactions are different among the three complexes. Bmf BH3 forms conserved hydrophobic and salt bridge interactions with Bcl-2 and Bcl-xL, and also establishes several hydrogen bonds to support their binding. However, the highly conserved Asp-Arg salt bridge is not formed in the Mcl-1/Bmf BH3 complex, and few hydrogen bonds are observed. Furthermore, mutational analysis shows that substitutions of less-conserved residues in the α2-α3 region of these pro-survival Bcl-2 family proteins, as well as the highly conserved Arg, lead to significant changes in their binding affinity to Bmf BH3, while substitutions of less-conserved residues in Bmf BH3 have a more dramatic effect on its affinity to Mcl-1. This study provides structural insight into the specificity and interaction mechanism of Bmf BH3 binding to pro-survival Bcl-2 family proteins, and helps guide the design of BH3 mimics targeting pro-survival Bcl-2 family proteins. Research Network of Computational and Structural Biotechnology 2023-07-21 /pmc/articles/PMC10407628/ /pubmed/37560128 http://dx.doi.org/10.1016/j.csbj.2023.07.017 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Article Wang, Haolan Guo, Ming Wei, Hudie Chen, Yongheng Structural basis of the specificity and interaction mechanism of Bmf binding to pro-survival Bcl-2 family proteins |
title | Structural basis of the specificity and interaction mechanism of Bmf binding to pro-survival Bcl-2 family proteins |
title_full | Structural basis of the specificity and interaction mechanism of Bmf binding to pro-survival Bcl-2 family proteins |
title_fullStr | Structural basis of the specificity and interaction mechanism of Bmf binding to pro-survival Bcl-2 family proteins |
title_full_unstemmed | Structural basis of the specificity and interaction mechanism of Bmf binding to pro-survival Bcl-2 family proteins |
title_short | Structural basis of the specificity and interaction mechanism of Bmf binding to pro-survival Bcl-2 family proteins |
title_sort | structural basis of the specificity and interaction mechanism of bmf binding to pro-survival bcl-2 family proteins |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10407628/ https://www.ncbi.nlm.nih.gov/pubmed/37560128 http://dx.doi.org/10.1016/j.csbj.2023.07.017 |
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