2. Academic Validation
  3. Inhibition of oligomeric BAX by an anti-apoptotic dimer

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

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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