Structural insight into the molecular mechanism of p53-mediated mitochondrial apoptosis

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 () and Yongheng Chen ()
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Hudie Wei: Central South University
Lingzhi Qu: Central South University
Shuyan Dai: Central South University
Yun Li: Central South University
Haolan Wang: Central South University
Yilu Feng: Central South University
Xiaojuan Chen: Central South University
Longying Jiang: Central South University
Ming Guo: Central South University
Jun Li: Central South University
Zhuchu Chen: Central South University
Lin Chen: University of Southern California
Ye Zhang: Central South University
Yongheng Chen: Central South University

Nature Communications, 2021, vol. 12, issue 1, 1-9

Abstract: Abstract The tumor suppressor p53 is mutated in approximately half of all human cancers. p53 can induce apoptosis through mitochondrial membrane permeabilization by interacting with and antagonizing the anti-apoptotic proteins BCL-xL and BCL-2. However, the mechanisms by which p53 induces mitochondrial apoptosis remain elusive. Here, we report a 2.5 Å crystal structure of human p53/BCL-xL complex. In this structure, two p53 molecules interact as a homodimer, and bind one BCL-xL molecule to form a ternary complex with a 2:1 stoichiometry. Mutations at the p53 dimer interface or p53/BCL-xL interface disrupt p53/BCL-xL interaction and p53-mediated apoptosis. Overall, our current findings of the bona fide structure of p53/BCL-xL complex reveal the molecular basis of the interaction between p53 and BCL-xL, and provide insight into p53-mediated mitochondrial apoptosis.

Date: 2021
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DOI: 10.1038/s41467-021-22655-6

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