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Structures of p53/BCL-2 complex suggest a mechanism for p53 to antagonize BCL-2 activity

Author

Listed:
  • Hudie Wei

    (Central South University)

  • Haolan Wang

    (Central South University)

  • Genxin Wang

    (Wuhan University
    Wuhan University)

  • Lingzhi Qu

    (Central South University)

  • Longying Jiang

    (Central South University
    Central South University)

  • Shuyan Dai

    (Central South University)

  • Xiaojuan Chen

    (Central South University)

  • Ye Zhang

    (Central South University)

  • Zhuchu Chen

    (Central South University)

  • Youjun Li

    (Wuhan University
    Wuhan University)

  • Ming Guo

    (Central South University)

  • Yongheng Chen

    (Central South University)

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.

Suggested Citation

  • Hudie Wei & Haolan Wang & Genxin Wang & Lingzhi Qu & Longying Jiang & Shuyan Dai & Xiaojuan Chen & Ye Zhang & Zhuchu Chen & Youjun Li & Ming Guo & Yongheng Chen, 2023. "Structures of p53/BCL-2 complex suggest a mechanism for p53 to antagonize BCL-2 activity," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40087-2
    DOI: 10.1038/s41467-023-40087-2
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    References listed on IDEAS

    as
    1. Douglas R. Green & Guido Kroemer, 2009. "Cytoplasmic functions of the tumour suppressor p53," Nature, Nature, vol. 458(7242), pages 1127-1130, April.
    2. Tilman Oltersdorf & Steven W. Elmore & Alexander R. Shoemaker & Robert C. Armstrong & David J. Augeri & Barbara A. Belli & Milan Bruncko & Thomas L. Deckwerth & Jurgen Dinges & Philip J. Hajduk & Mary, 2005. "An inhibitor of Bcl-2 family proteins induces regression of solid tumours," Nature, Nature, vol. 435(7042), pages 677-681, June.
    3. Richard W. Birkinshaw & Jia-nan Gong & Cindy S. Luo & Daisy Lio & Christine A. White & Mary Ann Anderson & Piers Blombery & Guillaume Lessene & Ian J. Majewski & Rachel Thijssen & Andrew W. Roberts & , 2019. "Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    4. Hudie Wei & Lingzhi Qu & Shuyan Dai & Yun Li & Haolan Wang & Yilu Feng & Xiaojuan Chen & Longying Jiang & Ming Guo & Jun Li & Zhuchu Chen & Lin Chen & Ye Zhang & Yongheng Chen, 2021. "Structural insight into the molecular mechanism of p53-mediated mitochondrial apoptosis," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
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