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The conformational stability of pro-apoptotic BAX is dictated by discrete residues of the protein core

Author

Listed:
  • Noah B. Bloch

    (Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute)

  • Thomas E. Wales

    (Northeastern University)

  • Michelle S. Prew

    (Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute)

  • Hannah R. Levy

    (Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute)

  • John R. Engen

    (Northeastern University)

  • Loren D. Walensky

    (Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute)

Abstract

BAX is a pro-apoptotic member of the BCL-2 family, which regulates the balance between cellular life and death. During homeostasis, BAX predominantly resides in the cytosol as a latent monomer but, in response to stress, transforms into an oligomeric protein that permeabilizes the mitochondria, leading to apoptosis. Because renegade BAX activation poses a grave risk to the cell, the architecture of BAX must ensure monomeric stability yet enable conformational change upon stress signaling. The specific structural features that afford both stability and dynamic flexibility remain ill-defined and represent a critical control point of BAX regulation. We identify a nexus of interactions involving four residues of the BAX core α5 helix that are individually essential to maintaining the structure and latency of monomeric BAX and are collectively required for dimeric assembly. The dual yet distinct roles of these residues reveals the intricacy of BAX conformational regulation and opportunities for therapeutic modulation.

Suggested Citation

  • Noah B. Bloch & Thomas E. Wales & Michelle S. Prew & Hannah R. Levy & John R. Engen & Loren D. Walensky, 2021. "The conformational stability of pro-apoptotic BAX is dictated by discrete residues of the protein core," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25200-7
    DOI: 10.1038/s41467-021-25200-7
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    Cited by:

    1. Michelle S. Prew & Christina M. Camara & Thomas Botzanowski & Jamie A. Moroco & Noah B. Bloch & Hannah R. Levy & Hyuk-Soo Seo & Sirano Dhe-Paganon & Gregory H. Bird & Henry D. Herce & Micah A. Gygi & , 2022. "Structural basis for defective membrane targeting of mutant enzyme in human VLCAD deficiency," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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