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Inhibition of oligomeric BAX by an anti-apoptotic dimer.

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Τίτλος: Inhibition of oligomeric BAX by an anti-apoptotic dimer.
Συγγραφείς: Newman CE; Department of Pediatric Oncology and Chemical Biology Program, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Gygi MA; Department of Pediatric Oncology and Chemical Biology Program, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Alimohamadi H; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA., DeAngelo TM; Department of Pediatric Oncology and Chemical Biology Program, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Camara CM; Department of Pediatric Oncology and Chemical Biology Program, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Mintseris J; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA., Yu E; Department of Pediatric Oncology and Chemical Biology Program, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Harvey EP; Department of Pediatric Oncology and Chemical Biology Program, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Hauseman ZJ; Department of Pediatric Oncology and Chemical Biology Program, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Fan L; SAXS Facility, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA., Wang YX; Center for Structural Biology, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA., Luo EW; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA., Godes M; Department of Pediatric Oncology and Chemical Biology Program, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Gehtman J; Department of Pediatric Oncology and Chemical Biology Program, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Cathcart AM; Department of Pediatric Oncology and Chemical Biology Program, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Gygi SP; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA., Engen JR; Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA., Bird GH; Department of Pediatric Oncology and Chemical Biology Program, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Wong GCL; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA., Wales TE; Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA., Walensky LD; Department of Pediatric Oncology and Chemical Biology Program, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: loren_walensky@dfci.harvard.edu.
Πηγή: Cell [Cell] 2025 Dec 24; Vol. 188 (26), pp. 7397-7412.e21. Date of Electronic Publication: 2025 Nov 21.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Cell Press Country of Publication: United States NLM ID: 0413066 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4172 (Electronic) Linking ISSN: 00928674 NLM ISO Abbreviation: Cell Subsets: MEDLINE
Imprint Name(s): Publication: Cambridge, Ma : Cell Press
Original Publication: Cambridge, MIT Press.
Ιατρικοί όροι (MeSH): bcl-2-Associated X Protein*/metabolism , bcl-2-Associated X Protein*/chemistry , bcl-2-Associated X Protein*/antagonists & inhibitors , Apoptosis*, Mitochondria/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Proto-Oncogene Proteins c-bcl-2/chemistry ; Humans ; Protein Multimerization ; Scattering, Small Angle ; Animals
Περίληψη: 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.
(Copyright © 2025 Elsevier Inc. All rights reserved.)
Competing Interests: Declaration of interests The authors report no competing interests.
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Grant Information: T32 GM144273 United States GM NIGMS NIH HHS; F30 CA275293 United States CA NCI NIH HHS; R35 CA197583 United States CA NCI NIH HHS; R50 CA211399 United States CA NCI NIH HHS; R01 GM067945 United States GM NIGMS NIH HHS; T32 HL069766 United States HL NHLBI NIH HHS; F31 CA210590 United States CA NCI NIH HHS; P30 GM133893 United States GM NIGMS NIH HHS; F31 CA210592 United States CA NCI NIH HHS; R01 DK117850 United States DK NIDDK NIH HHS; S10 OD012331 United States OD NIH HHS; 75N91019D00024 United States OD NIH HHS; F30 CA264846 United States CA NCI NIH HHS
Contributed Indexing: 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
Substance Nomenclature: 0 (bcl-2-Associated X Protein)
0 (Proto-Oncogene Proteins c-bcl-2)
Entry Date(s): Date Created: 20251122 Date Completed: 20251225 Latest Revision: 20260923
Update Code: 20260923
PubMed Central ID: PMC13200811
DOI: 10.1016/j.cell.2025.10.037
PMID: 41274283
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1097-4172
DOI:10.1016/j.cell.2025.10.037