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

Authors:
Open Access
Publisher website
Google Scholar
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.
Funding Information
  • National Natural Science Foundation of China (82172654, 819740748, 31900880, 82273496)
  • Department of Science and Technology of Hunan Province (2018RS3026, 2021RC4012)
  • China Postdoctoral Science Foundation (2019M652805)
  • Natural Science Foundation of Hunan Province
  • Natural Science Foundation of Hunan Province

This publication has 65 references indexed in Scilit: