Journal Article

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

Chen, Xiaojuan, Jiang, Longying, Li, Yun, Chen, Lin, Chen, Zhuchu, Wei, Hudie, Li, Jun, Dai, Shuyan, Qu, Lingzhi, Zhang, Ye, Wang, Haolan, Chen, Yongheng, Guo, Ming, Feng, Yilu

2021

Overview

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. The structure of human tumor suppressor p53 in complex with the antiapoptotic protein BCL-xL reveals the basis of the p53–BCL-xL interaction and provides insight into the mechanisms of p53-mediated mitochondrial apoptosis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/2 / 13/31 / 38/23 / 38/44 / 42/109 / 631/45/535/1266 / 631/45/612/1244 / 631/535/1266 / 631/67/1244 / 631/80/82/23 / 82/16 / 82/80 / 82/83 / Apoptosis / Apoptosis - genetics / Bcl-2 protein / Bcl-x protein / bcl-X Protein - genetics / bcl-X Protein - isolation & purification / bcl-X Protein - metabolism / bcl-X Protein - ultrastructure / Cell Line, Tumor / Crystal structure / Crystallography, X-Ray / Dimers / Humanities and Social Sciences / Humans / Mitochondria / Mitochondria - physiology / Molecular Docking Simulation / Molecular structure / multidisciplinary / Mutation / p53 Protein / Protein Binding - genetics / Protein Multimerization - genetics / Proteins / Recombinant Proteins - genetics / Recombinant Proteins - isolation & purification / Recombinant Proteins - metabolism / Recombinant Proteins - ultrastructure / Science / Science (multidisciplinary) / Stoichiometry / Tumor suppressor genes / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Protein p53 - isolation & purification / Tumor Suppressor Protein p53 - metabolism / Tumor Suppressor Protein p53 - ultrastructure / Tumors