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Isolation and Functional Analysis of Mitochondria from Cultured Cells and Mouse Tissue
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Structural insight into the molecular mechanism of p53-mediated mitochondrial apoptosis

Hudie Wei1, Lingzhi Qu1, Shuyan Dai1

  • 1Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Nature Communications
|April 17, 2021
PubMed

Insights

The tumor suppressor protein p53, mutated in many cancers, induces apoptosis by binding BCL-xL. This study reveals the p53/BCL-xL complex structure, clarifying how p53 triggers cell death.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Cancer Research

Background:

  • The tumor suppressor p53 is frequently mutated in human cancers.
  • p53 induces apoptosis via mitochondrial membrane permeabilization.
  • p53 antagonizes anti-apoptotic proteins BCL-xL and BCL-2, but the mechanism is unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism of p53-mediated mitochondrial apoptosis.
  • To determine the structural basis of the interaction between p53 and BCL-xL.

Main Methods:

  • X-ray crystallography of the human p53/BCL-xL complex.
  • Analysis of mutations at p53 and p53/BCL-xL interfaces.

Main Results:

  • A 2.5 Å crystal structure of the human p53/BCL-xL complex was determined.
  • The structure reveals a ternary complex with 2:1 stoichiometry (p53:BCL-xL).
  • Mutations disrupting p53 dimerization or the p53/BCL-xL interface abolish apoptosis.

Conclusions:

  • The study provides the bona fide structure of the p53/BCL-xL complex.
  • This structure reveals the molecular basis for p53's interaction with BCL-xL.
  • The findings offer insights into p53-mediated mitochondrial apoptosis and its role in cancer.

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