Structures of p53/BCL-2 complex suggest a mechanism for p53 to antagonize BCL-2 activity
Abstract Mitochondrial apoptosis is strictly controlled by BCL-2 family proteins through a subtle network of protein interactions. The tumor suppressor protein p53 triggers transcription-independent apoptosis through direct interactions with BCL-2 family proteins, but the molecular mechanism is not...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-40087-2 |
| _version_ | 1827895063988928512 |
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| author | Hudie Wei Haolan Wang Genxin Wang Lingzhi Qu Longying Jiang Shuyan Dai Xiaojuan Chen Ye Zhang Zhuchu Chen Youjun Li Ming Guo Yongheng Chen |
| author_facet | Hudie Wei Haolan Wang Genxin Wang Lingzhi Qu Longying Jiang Shuyan Dai Xiaojuan Chen Ye Zhang Zhuchu Chen Youjun Li Ming Guo Yongheng Chen |
| author_sort | Hudie Wei |
| collection | DOAJ |
| description | Abstract Mitochondrial apoptosis is strictly controlled by BCL-2 family proteins through a subtle network of protein interactions. The tumor suppressor protein p53 triggers transcription-independent apoptosis through direct interactions with BCL-2 family proteins, but the molecular mechanism is not well understood. In this study, we present three crystal structures of p53-DBD in complex with the anti-apoptotic protein BCL-2 at resolutions of 2.3–2.7 Å. The structures show that two loops of p53-DBD penetrate directly into the BH3-binding pocket of BCL-2. Structure-based mutations at the interface impair the p53/BCL-2 interaction. Specifically, the binding sites for p53 and the pro-apoptotic protein Bax in the BCL-2 pocket are mostly identical. In addition, formation of the p53/BCL-2 complex is negatively correlated with the formation of BCL-2 complexes with pro-apoptotic BCL-2 family members. Defects in the p53/BCL-2 interaction attenuate p53-mediated cell apoptosis. Overall, our study provides a structural basis for the interaction between p53 and BCL-2, and suggests a molecular mechanism by which p53 regulates transcription-independent apoptosis by antagonizing the interaction of BCL-2 with pro-apoptotic BCL-2 family members. |
| first_indexed | 2024-03-12T22:15:22Z |
| format | Article |
| id | doaj.art-db48de5db5fe4d37941c8b75ef220bd1 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-12T22:15:22Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-db48de5db5fe4d37941c8b75ef220bd12023-07-23T11:20:15ZengNature PortfolioNature Communications2041-17232023-07-0114111310.1038/s41467-023-40087-2Structures of p53/BCL-2 complex suggest a mechanism for p53 to antagonize BCL-2 activityHudie Wei0Haolan Wang1Genxin Wang2Lingzhi Qu3Longying Jiang4Shuyan Dai5Xiaojuan Chen6Ye Zhang7Zhuchu Chen8Youjun Li9Ming Guo10Yongheng Chen11Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratroy for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityDepartment of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratroy for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityHubei Key Laboratory of Cell Homeostasis, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan UniversityDepartment of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratroy for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityDepartment of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratroy for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityDepartment of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratroy for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityDepartment of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratroy for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityDepartment of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratroy for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityDepartment of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratroy for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityHubei Key Laboratory of Cell Homeostasis, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan UniversityDepartment of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratroy for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityDepartment of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratroy for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityAbstract Mitochondrial apoptosis is strictly controlled by BCL-2 family proteins through a subtle network of protein interactions. The tumor suppressor protein p53 triggers transcription-independent apoptosis through direct interactions with BCL-2 family proteins, but the molecular mechanism is not well understood. In this study, we present three crystal structures of p53-DBD in complex with the anti-apoptotic protein BCL-2 at resolutions of 2.3–2.7 Å. The structures show that two loops of p53-DBD penetrate directly into the BH3-binding pocket of BCL-2. Structure-based mutations at the interface impair the p53/BCL-2 interaction. Specifically, the binding sites for p53 and the pro-apoptotic protein Bax in the BCL-2 pocket are mostly identical. In addition, formation of the p53/BCL-2 complex is negatively correlated with the formation of BCL-2 complexes with pro-apoptotic BCL-2 family members. Defects in the p53/BCL-2 interaction attenuate p53-mediated cell apoptosis. Overall, our study provides a structural basis for the interaction between p53 and BCL-2, and suggests a molecular mechanism by which p53 regulates transcription-independent apoptosis by antagonizing the interaction of BCL-2 with pro-apoptotic BCL-2 family members.https://doi.org/10.1038/s41467-023-40087-2 |
| spellingShingle | Hudie Wei Haolan Wang Genxin Wang Lingzhi Qu Longying Jiang Shuyan Dai Xiaojuan Chen Ye Zhang Zhuchu Chen Youjun Li Ming Guo Yongheng Chen Structures of p53/BCL-2 complex suggest a mechanism for p53 to antagonize BCL-2 activity Nature Communications |
| title | Structures of p53/BCL-2 complex suggest a mechanism for p53 to antagonize BCL-2 activity |
| title_full | Structures of p53/BCL-2 complex suggest a mechanism for p53 to antagonize BCL-2 activity |
| title_fullStr | Structures of p53/BCL-2 complex suggest a mechanism for p53 to antagonize BCL-2 activity |
| title_full_unstemmed | Structures of p53/BCL-2 complex suggest a mechanism for p53 to antagonize BCL-2 activity |
| title_short | Structures of p53/BCL-2 complex suggest a mechanism for p53 to antagonize BCL-2 activity |
| title_sort | structures of p53 bcl 2 complex suggest a mechanism for p53 to antagonize bcl 2 activity |
| url | https://doi.org/10.1038/s41467-023-40087-2 |
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