Inhibition of oligomeric BAX by an anti-apoptotic dimer

  • Cell. 2025 Nov 21:S0092-8674(25)01242-5. doi: 10.1016/j.cell.2025.10.037.
Catherine E Newman  1 ,  Micah A Gygi  1 ,  Haleh Alimohamadi  2 ,  Thomas M DeAngelo  1 ,  Christina M Camara  1 ,  Julian Mintseris  3 ,  Ezra Yu  1 ,  Edward P Harvey  1 ,  Zachary J Hauseman  1 ,  Lixin Fan  4 ,  Yun-Xing Wang  5 ,  Elizabeth W-C Luo  2 ,  Marina Godes  1 ,  Jacob Gehtman  1 ,  Ann M Cathcart  1 ,  Steven P Gygi  3 ,  John R Engen  6 ,  Gregory H Bird  1 ,  Gerard C L Wong  2 ,  Thomas E Wales  6 ,  Loren D Walensky  7
Affiliations
  • 1. Department of Pediatric Oncology and Chemical Biology Program, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 2. Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 3. Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
  • 4. SAXS Facility, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
  • 5. Center for Structural Biology, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
  • 6. Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA.
  • 7. Department of Pediatric Oncology and Chemical Biology Program, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: [email protected].
PMID: 41274283 DOI: 10.1016/j.cell.2025.10.037
Abstract

Bax is a pro-apoptotic Bcl-2 protein that resides in the cytosol as a monomer until triggered by cellular stress to form an oligomer that permeabilizes mitochondria and induces Apoptosis. The paradigm for apoptotic blockade involves heterodimeric interactions between pro- and anti-apoptotic monomers. Here, we find that full-length Bcl-W forms a distinctive, symmetric dimer (Bcl-WD) that dissociates oligomeric Bax (BaxO), inhibits mitochondrial translocation, promotes retrotranslocation, blocks membrane-porating activity, and influences Apoptosis induction of cells. Structure-function analyses revealed discrete conformational changes upon Bcl-W dimerization and reciprocal structural impacts upon Bcl-WD and BaxO interaction. Small-angle X-ray scattering (SAXS) analysis demonstrated that BaxO disrupts membranes by inducing negative Gaussian curvature, which is reversed by positive Gaussian curvature exerted by Bcl-WD. Systematic truncation and mutagenesis dissected the core features of Bcl-WD activity-dimerization, BaxO engagement, and membrane interaction. Our studies reveal a downstream layer of apoptotic control mediated by protein and membrane interactions of higher-order Bcl-2 Family multimers.

Keywords
BAX; BCL-2 family proteins; BCL-w; anti-apoptotic; apoptosis; cell death; chemical crosslinking mass spectrometry; dimer; hydrogen deuterium exchange mass spectrometry; membrane curvature; mitochondria; mitochondrial retrotranslocation; mitochondrial translocation; oligomer; pro-apoptotic; small-angle X-ray scattering.
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