Affinage

BAX

Apoptosis regulator BAX · UniProt Q07812

Length
192 aa
Mass
21.2 kDa
Annotated
2026-06-09
100 papers in source corpus 40 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BAX is a pro-apoptotic BCL-2 family protein that executes mitochondrial outer membrane permeabilization (MOMP), the committed step of intrinsic apoptosis (PMID:9382873, PMID:26783362). In healthy cells BAX is held inactive in the cytosol as a conformational ensemble of monomers and an autoinhibited dimer in which the N-terminal α1 helix keeps the C-terminal α9 transmembrane signal-anchor sequestered in the dimerization pocket, preventing mitochondrial insertion (PMID:27425408, PMID:30122452, PMID:19917256, PMID:9763432). A death signal relieves this autoinhibition: direct-activator BH3-only proteins (tBID, BIM, PUMA) engage a distinct trigger site, expose α1, disengage α9, and drive mitochondrial targeting and homo-oligomerization, with BID acting catalytically and through both BID-dependent and BID-independent routes (PMID:19917256, PMID:22634637, PMID:11139284, PMID:20008353). Membrane-inserted BAX undergoes opening of the α5–α6 hairpin and assembles into symmetric dimers that further organize into rings, arcs, and linear oligomers forming pores of variable size (PMID:25458844, PMID:26783362, PMID:20008353). These pores enlarge into macropores permitting inner-membrane herniation and release of cytochrome c and mtDNA, the latter activating cGAS/STING innate-immune signaling (PMID:29472455, PMID:38830851). VDAC2 serves as the mitochondria-specific platform governing BAX association and is selectively required for BAX (not BAK) apoptotic function (PMID:30478310, PMID:27620692). BAX activity is opposed by pro-survival proteins—BCL-xL drives retrotranslocation of membrane BAX back to the cytosol, BCL-2 sequesters inserted monomers, and the BCL-2 BH4 domain noncanonically suppresses BAX N-terminal activation (PMID:21458670, PMID:16642033, PMID:25684204)—and by inhibitory phosphorylation at Ser184 by Akt and PKCζ that retains BAX in the cytosol (PMID:17525161, PMID:29987135). Beyond apoptosis, BAX promotes mitochondrial fusion by activating the GTPase Mfn2 in healthy cells and can also permeabilize endoplasmic reticulum and lysosomal membranes (PMID:17035996, PMID:12847083, PMID:24686337). The membrane environment, including mitochondrial size, cholesterol, and unsaturated lipids, tunes BAX integration and pore activity (PMID:25482509, PMID:18590739, PMID:38830851).

Mechanistic history

Synthesis pass · year-by-year structured walk · 34 steps
  1. 1997 High

    Established that BAX is a cytosolic protein that relocates to mitochondria at the onset of apoptosis and that its C-terminal hydrophobic domain is essential for both targeting and killing, defining the spatial logic of BAX activation.

    Evidence GFP-fusion live-cell confocal microscopy, FRAP, and domain-deletion death assays in Cos-7/L929 cells

    PMID:9382873

    Open questions at the time
    • Did not define what represses targeting in healthy cells
    • Molecular trigger for translocation unresolved
  2. 1998 High

    Showed that the N-terminal domain represses the C-terminal signal-anchor and that a death signal (partly caspase-dependent) relieves this, explaining how membrane insertion is held in check until apoptosis.

    Evidence Domain/chimeric mutagenesis, in vivo and cell-free targeting reconstitution, zVAD-fmk inhibition

    PMID:9763432

    Open questions at the time
    • Identity of the relieving factor not pinned down
    • Caspase role only partial
  3. 2000 High

    Identified tBID as a trigger that relieves N-terminal repression of insertion, while revealing a parallel BID-independent route and uncoupling cytochrome c release from BAX insertion under some conditions.

    Evidence In vivo/in vitro mitochondrial targeting reconstitution and Bid-null MEF genetics

    PMID:11139284

    Open questions at the time
    • Nature of the BID-independent pathway unresolved
    • Stoichiometry of activation not defined
  4. 2003 High

    Demonstrated BAX/BAK act at the ER as well as mitochondria, defining a parallel ER-stress caspase-12 pathway and broadening BAX's organellar reach.

    Evidence Organelle-targeted Bak mutants in bax-/-bak-/- cells, caspase-12 cleavage and ER Ca2+ assays

    PMID:12847083

    Open questions at the time
    • How BAX selects ER vs mitochondria unclear
    • Relevance of caspase-12 pathway across species
  5. 2004 High

    Identified ASC as a p53-dependent adaptor coupling genotoxic stress to BAX mitochondrial translocation, linking upstream stress signaling to BAX activation.

    Evidence Co-IP, siRNA knockdown, colocalization, caspase activation assays

    PMID:14730312

    Open questions at the time
    • Direct binding interface not mapped
    • Whether ASC activates or merely chaperones BAX unclear
  6. 2006 High

    Revealed a non-death role: BAX promotes mitochondrial fusion in healthy cells by activating Mfn2, showing BAX function is not restricted to apoptosis.

    Evidence Bax/Bak knockout cells, live-cell morphology imaging, Mfn2 distribution/mobility studies

    PMID:17035996

    Open questions at the time
    • Direct biochemical mechanism of Mfn2 activation undefined
    • How this role is partitioned from apoptotic function unclear
  7. 2006 Medium

    Showed BCL-2 sequesters membrane-inserted BAX monomers via a tBid/Bax-induced conformational change requiring α5–α6 helix mobility, defining a post-insertion inhibitory checkpoint.

    Evidence Disulfide-tethered BCL-2 mutant in cells and isolated mitochondria

    PMID:16642033

    Open questions at the time
    • Engineered mutant; physiological conformer not directly observed
    • Single lab
  8. 2007 High

    Established direct phosphorylation of BAX at Ser184 by PKCζ as a survival switch that prevents conformational change and dissociates BAX from mitochondria, defining post-translational suppression.

    Evidence In vitro kinase assay with purified proteins, phospho-site mutagenesis, Co-IP, mitochondrial dissociation assay

    PMID:17525161

    Open questions at the time
    • Physiological contexts of PKCζ regulation of BAX limited
    • Structural basis of S184 effect not resolved
  9. 2009 High

    Defined the stepwise activation mechanism whereby α1 keeps α9 in the dimerization pocket and direct activators expose α1 to release α9, with activators remaining engaged to drive oligomerization.

    Evidence Domain mutagenesis, structural analysis, cellular targeting/oligomerization and BH3 interaction assays

    PMID:19917256

    Open questions at the time
    • Transient nature of activator engagement not quantified
    • Membrane requirement not addressed structurally
  10. 2009 High

    Provided a biophysical oligomer model showing BH3:groove dimers nucleate assembly and that BID acts catalytically, establishing the structural unit of the BAX pore.

    Evidence EPR with spin-labeled Bax, AFM, cryo-EM, liposome reconstitution

    PMID:20008353

    Open questions at the time
    • Higher-order assembly geometry incompletely resolved
    • Pore lipidic vs proteinaceous nature unsettled
  11. 2009 Medium

    Showed BAX transiently activates endophilin B1 oligomerization to vesiculate membranes, implicating BAX in mitochondrial membrane remodeling beyond pore formation.

    Evidence Cell-free reconstitution with purified proteins, SEC, GUV vesiculation assay

    PMID:19805544

    Open questions at the time
    • In vitro only; cellular relevance not established
    • BAX does not stably associate, so mechanism transient and hard to validate
  12. 2011 High

    Defined BCL-xL inhibition as continuous retrotranslocation of membrane BAX back to the cytosol, reframing pro-survival control as a dynamic spatial mechanism rather than static sequestration.

    Evidence Disulfide tethering, FLIP, cell-free MOMP assay, Co-IP

    PMID:21458670

    Open questions at the time
    • Molecular machinery of transport step not fully defined
    • How activation overrides retrotranslocation unclear
  13. 2011 Medium

    Identified HDAC6/Ku70 as a cytosolic restraint that holds BAX inactive in a deacetylated-Ku70 complex, linking acetylation status to BAX availability.

    Evidence Co-IP, HDAC6 inhibitor, siRNA knockdown, cell death assay in neuroblastoma

    PMID:21847364

    Open questions at the time
    • Direct vs indirect binding not separated
    • Generality beyond neuroblastoma untested
  14. 2012 High

    Identified a distinct BAX trigger site by NMR using a direct small-molecule activator, establishing that BAX can be activated independently of antiapoptotic proteins or BAK.

    Evidence Computational screen, NMR interaction analysis, oligomerization and death assays

    PMID:22634637

    Open questions at the time
    • In-cell occupancy of the trigger site not measured
    • Endogenous ligand of trigger site unknown at this stage
  15. 2012 High

    Solved the BAX-vMIA complex by NMR, revealing a viral inhibitory site distinct from canonical surfaces, illustrating an additional regulatable surface on BAX.

    Evidence NMR structure of BAX-vMIA peptide, cellular localization and cytochrome c assays, interface rescue mutagenesis

    PMID:23213219

    Open questions at the time
    • Physiological host counterpart of this site unknown
    • Mechanism limited to viral context
  16. 2014 High

    Determined an in-membrane structural model showing active BAX as dimer assemblies with a flexible piercing domain and α5–α6 clamp opening as the central permeabilizing change.

    Evidence DEER EPR spectroscopy in liposomes and isolated mitochondria

    PMID:25458844

    Open questions at the time
    • Atomic-resolution pore structure still lacking
    • Higher-order ring/arc connectivity not resolved here
  17. 2014 Medium

    Showed BAX can directly permeabilize lysosomal membranes early in Parkinson disease models, extending pore activity to a non-mitochondrial organelle.

    Evidence Recombinant BAX LMP assay in purified lysosomes, channel inhibitor, in vivo/in vitro translocation

    PMID:24686337

    Open questions at the time
    • Targeting determinants for lysosomes vs mitochondria unknown
    • Single disease model
  18. 2015 High

    Defined a noncanonical inhibitory mechanism in which the BCL-2 BH4 domain binds a defined groove on BAX to suppress N-terminal activation, distinct from BH3-groove sequestration.

    Evidence HDX-MS, fluorescence polarization binding, BAX activation assay

    PMID:25684204

    Open questions at the time
    • Cellular contribution relative to canonical sequestration unquantified
    • Structural complex not crystallized
  19. 2015 Medium

    Showed mitochondrial size controlled by Mfn1-mediated fusion is required for productive BAX α9·membrane interactions, linking organelle morphology to permeabilization competence.

    Evidence Mfn1 manipulation, size-restricted OMM models, BAX binding and MOMP assays in vitro/in vivo

    PMID:25482509

    Open questions at the time
    • Biophysical basis of size dependence incomplete
    • Single lab
  20. 2015 Medium

    Identified PGAM5L as required for BAX activation/translocation via a Bax-PGAM5L-Drp1 ternary complex, connecting BAX to the fission machinery.

    Evidence Co-IP, siRNA, Bax-null rescue, GFP-Bax translocation, tumor models

    PMID:26356820

    Open questions at the time
    • Direct vs scaffold role of PGAM5L unclear
    • Interaction interfaces unmapped
  21. 2015 Medium

    Showed DRAM1 binds BAX, blocks its autophagic degradation, and recruits it to lysosomes to initiate a cathepsin B–tBID amplification loop, defining a lysosome-initiated apoptotic route for BAX.

    Evidence Co-IP, stability assay, lysosomal fractionation, cathepsin B and cytochrome c release assays

    PMID:25633293

    Open questions at the time
    • Direct binding interface unmapped
    • Generality of lysosomal BAX route uncertain
  22. 2016 High

    Visualized BAX organizing into rings, arcs, and linear assemblies that perforate membranes, establishing that pores can be fully or partially delineated and vary in size.

    Evidence Dual-color SMLM super-resolution and AFM on lipid bilayers

    PMID:26783362

    Open questions at the time
    • Lipidic vs proteinaceous pore character unresolved
    • Determinants of arc vs ring choice unknown
  23. 2016 High

    Solved the autoinhibited inactive BAX dimer crystal structure, showing an asymmetric interaction that must dissociate to monomers before activation, defining a cytosolic restraint state.

    Evidence Full-length crystal structure, cellular activity and dimerization assays

    PMID:27425408

    Open questions at the time
    • Fraction of BAX in dimer vs monomer in cells unclear
    • Trigger for dissociation undefined
  24. 2016 Medium

    Established VDAC2 as the mitochondrial platform ensuring mitochondria-specific BAX retrotranslocation, also tuned by nucleotides and calcium.

    Evidence Mitochondrial isolation, retrotranslocation assay, VDAC2 deletion, localization analysis

    PMID:27620692

    Open questions at the time
    • Mechanism of VDAC2-BAX coupling not structurally defined
    • Where BAX goes without VDAC2 only partly characterized
  25. 2017 High

    Identified an allosteric sensitizer pocket at the α3–α4/α5–α6 junction that mobilizes the α1–α2 loop and BAX BH3 helix, mapping a druggable activation-promoting surface.

    Evidence NMR fragment screen, HDX-MS, biochemical activation assay

    PMID:28692068

    Open questions at the time
    • In-cell efficacy of sensitizers limited
    • Endogenous ligand of pocket unknown
  26. 2018 High

    Showed BAK/BAX macropores allow inner-membrane herniation and mtDNA release that activates cGAS/STING, connecting MOMP to innate immune signaling.

    Evidence Lattice light-sheet and super-resolution imaging of MEFs with BAK/BAX knockout

    PMID:29472455

    Open questions at the time
    • Molecular control of macropore enlargement unclear
    • Timing relative to caspase activation not fully mapped
  27. 2018 High

    Established Akt phosphorylation at Ser184 as an apoptosis-to-survival switch that lets BAX bind and sequester activator BH3 proteins while blocking insertion, defining a converging Ser184 regulatory node.

    Evidence Phospho-mutagenesis, BH3 binding assay, insertion and apoptosis-resistance assays

    PMID:29987135

    Open questions at the time
    • Structural basis of converted BH3-binding behavior unresolved
    • Interplay with PKCζ at the same site untested
  28. 2018 High

    Demonstrated cytosolic BAX is a conformational ensemble whose distribution sets function, with structures showing α9 exposure as the key tunable element.

    Evidence Crystal structures of BAX P168G and BAX-3C10 antibody complex, inhibition assays

    PMID:30122452

    Open questions at the time
    • How upstream signals bias the ensemble undefined
    • Quantitative populations in cells unknown
  29. 2018 High

    Established VDAC2 as selectively required for BAX (not BAK) apoptotic function via an unbiased screen, defining a BAX-specific dependency.

    Evidence Genome-wide CRISPR screen, VDAC2 deletion, Co-IP, tumor formation assays

    PMID:30478310

    Open questions at the time
    • Whether VDAC2 directly forms the pore platform vs acts as receptor unclear
    • Structural BAX-VDAC2 interface unresolved
  30. 2018 Medium

    Showed Parkin suppresses BAX indirectly (no BAX ubiquitination), contrasting with direct BAK ubiquitination and revealing mechanistic divergence between the two effectors during mitophagy.

    Evidence Ubiquitination assay, BAX/BAK-deficient analysis, mitophagy and apoptosis assays

    PMID:30573668

    Open questions at the time
    • Indirect mechanism not defined
    • Negative finding; intermediary unknown
  31. 2019 High

    Defined an allosteric inhibitory pocket near α5 targeted by small-molecule BAIs that stabilize the hydrophobic core and block translocation/oligomerization, providing a pharmacological off-switch.

    Evidence NMR binding, biochemical activation, cellular translocation/oligomerization assays

    PMID:30718816

    Open questions at the time
    • In-cell selectivity and potency limited
    • No endogenous regulator of this pocket identified
  32. 2019 Medium

    Identified cytoplasmic cyclin C, released during oxidative stress, as a direct BAX-binding factor required for efficient activation and mitochondrial localization, linking stress-driven nuclear release to BAX.

    Evidence Co-IP of endogenous proteins, in vitro binding with recombinant BAX, localization assays

    PMID:31385392

    Open questions at the time
    • Binding interface unmapped
    • Requirement for fission complex mechanistically unexplained
  33. 2022 High

    Showed BAX physically interacts with DRP1 in membranes via its N-terminus and that DRP1 can act as a noncanonical direct activator, integrating the fission GTPase into BAX activation.

    Evidence Reciprocal Co-IP, super-resolution imaging, forced dimerization, permeabilization assay

    PMID:35023587

    Open questions at the time
    • How DRP1 activation compares to BH3-only activators unclear
    • In vivo contribution to apoptosis not quantified
  34. 2024 High

    Demonstrated that unsaturated lipids enrich around BAX/BAK and promote pore activity, and that FADS2 enhances apoptosis and cGAS/STING activation, defining lipid composition as a determinant of permeabilization.

    Evidence Comparative lipidomics in nanodiscs, pore assays in model membranes/mitochondria/cells, FADS2 manipulation, MD simulations

    PMID:38830851

    Open questions at the time
    • Mechanism by which unsaturation favors integration not atomically defined
    • Physiological regulation of local lipid pool unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved whether the BAX pore is fundamentally lipidic, proteinaceous, or hybrid, and what unifies the diverse activating inputs (BH3-only proteins, DRP1, cyclin C, PGAM5L, ASC, prostaglandins) into a single quantitative model of pore formation.
  • No atomic-resolution structure of the assembled BAX pore
  • No integrated kinetic model reconciling the many activators and inhibitors
  • Determinants of organelle selectivity (mitochondria vs ER vs lysosome) undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0008289 lipid binding 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005739 mitochondrion 4 GO:0005829 cytosol 4 GO:0005764 lysosome 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-5357801 Programmed Cell Death 4 R-HSA-168256 Immune System 2 R-HSA-1852241 Organelle biogenesis and maintenance 2
Partners
BCL2BCL2L1BIDDNM1LMFN2PGAM5PYCARDVDAC2

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Bax resides as a soluble cytosolic protein in healthy cells and translocates to mitochondria early during apoptosis (before nuclear condensation). Removal of the C-terminal hydrophobic domain inhibits this redistribution and abolishes death-promoting activity, demonstrating the C-terminal domain is required for both mitochondrial targeting and pro-apoptotic function. GFP-fusion live-cell confocal microscopy, FRAP, domain deletion mutagenesis in Cos-7 and L929 cells The Journal of cell biology High 9382873
1998 Regulated mitochondrial membrane insertion of BAX is governed by discrete domains: the N-terminal domain represses the transmembrane signal-anchor function of the C-terminal domain, and in unstimulated cells this prevents mitochondrial insertion. A death signal relieves this inhibition; caspase activity (blocked by zVAD-fmk) partially mediates stimulated mitochondrial membrane insertion in vivo and is required in cell-free apoptotic extracts. Deletion and chimeric domain mutagenesis of BAX, in vivo targeting assays, cell-free mitochondrial targeting reconstitution, zVAD-fmk inhibitor treatment The Journal of cell biology High 9763432
2011 Bcl-xL inhibits BAX by constantly retrotranslocating membrane-associated BAX from mitochondria back into the cytoplasm. FLIP analysis shows WT Bax but not conformationally tethered Bax undergoes retrotranslocation; inhibition of retrotranslocation causes BAX accumulation on mitochondria. Pro-survival BCL-2 family proteins are required for this retrotranslocation. Intramolecular disulfide tethering, fluorescence loss in photobleaching (FLIP), cell-free MOMP assay, Co-IP in detergents Cell High 21458670
2009 BAX activation proceeds via stepwise structural reorganization: the α1 helix of BAX keeps the α9 helix engaged in the dimerization pocket, maintaining BAX as a cytosolic monomer. Direct-activator BH3-only proteins (tBID, BIM, PUMA) engage and expose the α1 helix, causing disengagement of α9 and mitochondrial insertion; these activators remain associated with N-terminally exposed BAX through the BH1 domain to drive homo-oligomerization. Domain mutagenesis, structural analysis, cell-based BAX targeting and oligomerization assays, BH3-only protein interaction studies Molecular cell High 19917256
2014 A structural model of active membrane-inserted BAX was determined by DEER spectroscopy in liposomes and isolated mitochondria. Active BAX is organized as assemblies of dimers; each monomer contains a stable dimerization domain and a flexible piercing domain. The primary structural change during activation is opening of the α5-α6 hairpin into a clamp-like conformation central to mitochondrial membrane permeabilization. Double electron-electron resonance (DEER) EPR spectroscopy in liposomes and isolated mitochondria Molecular cell High 25458844
2006 In healthy cells, Bax (and Bak) is required for normal mitochondrial fusion. Bax promotes mitochondrial fusion by activating assembly of the large GTPase Mfn2 and altering its submitochondrial distribution and membrane mobility, properties that correlate with different GTP-bound states of Mfn2. Bax/Bak knockout cell analysis, live-cell imaging of mitochondrial morphology, Mfn2 distribution and mobility studies Nature High 17035996
2018 BAK/BAX form macropores in the mitochondrial outer membrane during apoptosis that are large enough to allow the inner mitochondrial membrane to herniate into the cytosol, carrying mitochondrial matrix components including mtDNA, thereby enabling cGAS/STING pathway activation. Live-cell lattice light-sheet microscopy of mouse embryonic fibroblasts, super-resolution imaging, BAK/BAX genetic knockout Science High 29472455
2016 Active BAX clusters into distinct ring, arc, and linear oligomeric assemblies at mitochondria during apoptosis. Both complete rings and arc-shaped assemblies perforate the membrane, supporting a mechanism where BAX fully or partially delineates pores of different sizes. Dual-color single-molecule super-resolution localization microscopy, atomic force microscopy on lipid bilayers The EMBO journal High 26783362
2018 VDAC2 is specifically required for BAX (but not BAK) apoptotic function. Genetic deletion of VDAC2 abrogates BAX association with mitochondrial VDAC complexes and inhibits BAX-mediated apoptosis, phenocopying BAX loss in tumor suppression assays. Genome-wide CRISPR/Cas9 screen, VDAC2 genetic deletion, co-immunoprecipitation, tumor formation assays Nature communications High 30478310
2016 VDAC2 serves as the mitochondrial platform for Bax retrotranslocation, ensuring mitochondria-specific membrane association of Bax. In the absence of VDAC2, Bax localizes to other cell compartments. Bax retrotranslocation is also regulated by nucleotides and calcium ions. Mitochondrial isolation, Bax retrotranslocation assay, VDAC2 genetic deletion, localization analysis Scientific reports Medium 27620692
2003 Bax and Bak can localize to the endoplasmic reticulum as well as to mitochondria. At the ER, Bax/Bak undergo conformational changes and oligomerization upon ER stress, leading to caspase-12 cleavage, progressive ER Ca2+ depletion, and a parallel caspase activation pathway distinct from the mitochondrial pathway. Organelle-targeted Bak mutant expression in bax-/-bak-/- cells, caspase-12 cleavage assay, ER Ca2+ measurement, caspase-7/PARP cleavage The Journal of cell biology High 12847083
2012 A small molecule (BTSA1-related compound) directly activates BAX by engaging the BAX trigger site (a distinct BH3-binding groove on BAX) as confirmed by NMR. Binding at this site promotes BAX oligomerization and induces BAX-dependent cell death without interacting with antiapoptotic BCL-2 proteins or BAK. Computational screening, NMR interaction analysis, biochemical oligomerization assay, BAX-dependent cell death assay Nature chemical biology High 22634637
2015 The BCL-2 BH4 domain binds to a groove on BAX formed by α1, α1-α2 loop, and α2-α3/α5-α6 hairpins with nanomolar affinity, independently inhibiting BAX conformational activation. Hydrogen-deuterium exchange MS showed BH4 suppresses BIM BH3-induced N-terminal conformational changes in BAX—a noncanonical inhibitory mechanism distinct from the canonical BH3-groove sequestration. Hydrogen-deuterium exchange mass spectrometry, fluorescence polarization binding assay, structural localization by HDX-MS, BAX activation assay Molecular cell High 25684204
2016 Cytosolic BAX exists in an autoinhibited inactive dimer conformation in addition to the monomer. Crystal structure of the inactive BAX dimer reveals an asymmetric interaction that inhibits the N-terminal conformational change of one protomer and displaces the C-terminal α9 helix of the second. This dimer must dissociate to monomers before BAX can be activated. Full-length crystal structure determination, cellular BAX activity assays, biochemical dimerization analysis Molecular cell High 27425408
2019 Small-molecule BAX inhibitors (BAIs) bind directly to a previously unrecognized pocket around helix α5 on BAX and allosterically inhibit BAX activation by stabilizing the hydrophobic core, preventing conformational changes required for mitochondrial translocation and oligomerization. NMR binding assay, biochemical BAX activation assay, cellular translocation and oligomerization analysis Nature chemical biology High 30718816
2017 An NMR fragment screen identified a compound that sensitizes BAX activation by binding to a pocket at the junction of α3-α4 and α5-α6 hairpins, allosterically mobilizing the α1-α2 loop and BAX BH3 helix—two motifs implicated in activation and oligomerization of BAX. NMR-based fragment screen, HDX-MS structural analysis, biochemical BAX activation assay Nature chemical biology High 28692068
2022 BAX physically interacts with DRP1, and this interaction is enhanced during apoptosis. Complex formation occurs exclusively in the membrane environment and requires the BAX N-terminal region. Forced dimerization of BAX and DRP1 triggers their co-activation and translocation to mitochondria, inducing mitochondrial remodeling and permeabilization. DRP1 can act as a noncanonical direct activator of BAX. Co-immunoprecipitation, super-resolution microscopy, forced dimerization constructs, mitochondrial permeabilization assay The EMBO journal High 35023587
2004 ASC (apoptosis-associated speck-like protein) functions as an adaptor for BAX, directly interacting with BAX and colocalizing it to mitochondria. ASC induces cytochrome c release, reduces mitochondrial membrane potential, and activates caspase-9, -2, and -3. siRNA knockdown of ASC impairs BAX mitochondrial translocation in response to p53 or genotoxic stress. ASC induction after genotoxic stress depends on p53. Co-immunoprecipitation, siRNA knockdown, colocalization microscopy, caspase activation assay, mitochondrial membrane potential assay Nature cell biology High 14730312
2005 RASSF1A activates BAX via the Bax-binding protein MOAP-1. RASSF1A directly interacts with MOAP-1, and this interaction is enhanced by activated K-Ras. RASSF1A, MOAP-1, and activated K-Ras synergize to induce BAX activation and cell death. A tumor-derived RASSF1A point mutant defective for MOAP-1 interaction fails to activate BAX. Co-immunoprecipitation, BAX activation assay, shRNA knockdown, point mutant analysis The Journal of biological chemistry Medium 16344548
2007 PKCζ directly phosphorylates BAX at serine 184 in vitro and in vivo. This phosphorylation prevents BAX conformational change and mitochondrial translocation, sequesters BAX in the cytoplasm, and prolongs cell survival. Purified PKCζ can directly dissociate BAX from isolated mitochondria of ceramide-treated cells. PKCζ and BAX interact at the BH3 domain. In vitro kinase assay with purified PKCζ and BAX, phospho-site-specific mutagenesis, co-immunoprecipitation, BAX mitochondrial dissociation assay, siRNA knockdown The Journal of biological chemistry High 17525161
2018 Akt phosphorylates BAX at serine S184, converting BAX from pro-apoptotic to anti-apoptotic. Mechanistically, S184 phosphorylation enables BAX to bind pro-apoptotic activator BH3 proteins in solution, and prevents BAX insertion into mitochondria. This promotes sequestration of activator BH3 proteins and resistance to apoptosis. Phospho-site mutagenesis, BH3 protein binding assay, mitochondrial insertion assay, cellular apoptosis resistance assay EMBO reports High 29987135
2011 HDAC6 binds both Ku70 and BAX in the cytoplasm of neuroblastoma cells and maintains Ku70 in a deacetylated state that keeps BAX complexed with Ku70. Knockdown of HDAC6 or use of an HDAC6-specific inhibitor triggers Ku70 acetylation, BAX release from Ku70, and BAX-dependent cell death. Co-immunoprecipitation, HDAC6-specific inhibitor treatment, siRNA knockdown, cell death assay Neoplasia Medium 21847364
2000 tBID (caspase-8 cleavage product of BID) directly or indirectly relieves inhibition of the BAX transmembrane signal-anchor by the N-terminal domain, resulting in BAX integration into mitochondrial membrane. However, a BID-independent pathway for BAX mitochondrial insertion also exists (shown in Bid-null MEFs), and cytochrome c release can be uncoupled from BAX membrane insertion in the absence of BID. In vivo and in vitro mitochondrial targeting reconstitution, Bid-null MEF genetics, caspase-8 cleavage assay Cell death and differentiation High 11139284
2009 Bid activates BAX independently of stoichiometric ratio, suggesting Bid has a catalytic (transient) function. The nucleation event for BAX homo-oligomerization is formation of a stable dimerization interface involving two BH3 domains. EPR-based intermolecular distance measurements yielded a model of six adjacent BAX molecules where hydrophobic hairpins (helices α5-α6) are equally spaced in the membrane. Electron paramagnetic resonance (EPR) with spin-labeled Bax, atomic force microscopy, cryo-electron microscopy, liposome reconstitution The Journal of biological chemistry High 20008353
2006 BCL-2 undergoes a conformational change in the mitochondrial membrane in response to apoptotic agonists (tBid, Bax). This conformational change is required to sequester membrane-inserted BAX monomers and prevent productive BAX oligomerization. A disulfide-tethered BCL-2 mutant (S105C/E152C) that restricts α5-α6 helix mobility is only active in reducing conditions, confirming helix mobility is required. Disulfide-tethered BCL-2 mutant, transfected cell and isolated mitochondria assays, tBid-induced oligomerization assay The EMBO journal Medium 16642033
2012 Human cytomegalovirus vMIA inhibits BAX by binding to a previously unknown regulatory site on BAX (distinct from canonical interaction sites), as determined by NMR structure of the BAX-vMIA peptide complex. Binding stabilizes key elements required for BAX MOM insertion and oligomerization. Mutants disrupting key intermolecular interactions impair vMIA-mediated mitochondrial recruitment of BAX and increase cytochrome c release. NMR structure determination of BAX-vMIA peptide complex, cellular BAX localization assay, cytochrome c release assay, charge-reversal interface rescue mutagenesis PNAS High 23213219
2007 Bnip3 mediates mitochondrial dysfunction and cell death through Bax and Bak as downstream effectors. BAX/BAK double-deficient MEFs are completely resistant to hypoxia-induced cell death and Bnip3 overexpression, and re-expression of either Bax or Bak restores susceptibility. Bnip3 triggers GFP-Bax translocation to mitochondria during simulated ischemia-reperfusion. Bax/Bak double-knockout MEFs, genetic rescue with Bax or Bak re-expression, GFP-Bax live-cell imaging, mitochondrial membrane potential and cytochrome c assays The Biochemical journal Medium 17447897
2015 Mitochondrial size controlled by Mfn1-mediated fusion is required for productive BAX-membrane interactions. Cells with hyperfragmented mitochondria fail to support BAX-dependent membrane association and permeabilization due to an inability to stabilize BAX α9·membrane interactions. This was demonstrated in biochemical, cellular, in vivo, and size-restricted OMM model systems. Mfn1 genetic manipulation, size-restricted OMM model systems, BAX binding assay, MOMP measurement, in vivo and ex vivo studies Molecular cell Medium 25482509
2021 Eltrombopag (FDA-approved drug) directly inhibits BAX by binding the BAX trigger site, preventing BH3-only activators from triggering BAX conformational transformation and simultaneously stabilizing the inactive BAX structure, thereby inhibiting BAX-mediated apoptosis. NMR binding assay, BAX conformational activation assay, cellular apoptosis assay Nature communications High 33602934
2018 Parkin suppresses BAX-mediated apoptosis through an indirect mechanism (not via direct BAX ubiquitination), in contrast to its direct ubiquitination of BAK. The indirect mechanism of BAX suppression by Parkin during mitophagy was established by the absence of BAX ubiquitination alongside functional suppression of BAX activity. Ubiquitination assay, BAX/BAK-deficient genetic analysis, mitophagy induction, apoptosis assay The EMBO journal Medium 30573668
2015 PGAM5L (long isoform) is required for Bax activation and its translocation to mitochondria during intrinsic apoptosis. A Bax-PGAM5L-Drp1 ternary complex forms during apoptosis; Bax transfection rescues triplex formation in Bax-null cells. Knockdown of PGAM5L inhibits Bax translocation and reduces mitochondrial fission. Co-immunoprecipitation, siRNA knockdown, Bax-null cell rescue, GFP-Bax translocation assay, in vivo tumor models Oncotarget Medium 26356820
2019 Cyclin C, released from the nucleus to cytoplasm during oxidative stress, directly co-immunoprecipitates with active BAX and binds recombinant BAX in vitro. Cytoplasmic cyclin C is required for both normal BAX activation and efficient BAX mitochondrial localization. Stable cyclin C-BAX association requires the fission complex. Co-immunoprecipitation of endogenous proteins, in vitro binding with recombinant BAX, cyclin C nuclear release manipulation, BAX activation and localization assay EMBO reports Medium 31385392
2009 Bax activates endophilin B1 (Endo B1) oligomerization in a cell-free system: purified Bax induces Endo B1 to assemble into high-molecular-weight oligomers via the Endo B1 C-terminal SH3 domain, without Bax stably associating with the final complex. Together, Bax plus Endo B1 induces massive vesiculation of giant unilamellar vesicles, suggesting Bax regulates mitochondrial membrane remodeling via transient Endo B1 activation. Cell-free reconstitution with purified proteins, size-exclusion chromatography, giant unilamellar vesicle assay The Journal of biological chemistry Medium 19805544
2010 Prostaglandin E2 (PGE2) directly binds BAX and induces a conformational change that triggers apoptosis. Cys126 in the loop between the two transmembrane α-helices is critical for PGE2-induced BAX activation. PGD2 antagonizes PGE2 binding to BAX and inhibits PGE2-induced apoptosis, establishing a PGE2/PGD2 balance as a regulatory mechanism for BAX activation. Direct binding assay (PGE2-BAX), cysteine mutagenesis, apoptosis assays with multiple stimuli Cell death and differentiation Medium 20966963
2014 BAX directly permeabilizes lysosomal membranes (lysosomal membrane permeabilization, LMP) in Parkinson disease models. Recombinant BAX induces LMP in purified mouse brain lysosomes; pharmacological blockade of BAX channel activity prevents LMP. BAX translocates to lysosomal membranes early after MPTP treatment, preceding mitochondrial permeabilization. Recombinant BAX LMP assay in purified lysosomes, BAX channel inhibitor treatment, in vivo and in vitro BAX translocation assay Autophagy Medium 24686337
2008 Cholesterol in membrane bilayers inhibits BAX pore-forming activity by reducing the ability of BAX to transition from a membrane-associated to a membrane-integral state. Cholesterol increases BAX binding to membranes but markedly reduces integration into both liposomal and mitochondrial membranes. In vitro BAX membrane binding/integration assay with defined liposomes and isolated human mitochondria, cholesterol titration Journal of molecular biology Medium 18590739
2024 Unsaturated lipids are enriched in the proximal membrane environment of BAX and BAK during apoptosis. Unsaturated lipids promote BAX pore activity in model membranes, isolated mitochondria, and cellular systems. The fatty acid desaturase FADS2 enhances both apoptosis sensitivity and cGAS/STING pathway activation downstream of mtDNA release. Comparative lipidomics of BAK in lipid nanodiscs, BAX pore activity assay in model membranes and isolated mitochondria, FADS2 manipulation, molecular dynamics simulations Nature communications High 38830851
2008 TCTP antagonizes apoptosis by inserting into the mitochondrial membrane and inhibiting BAX dimerization. Crystal structure of human TCTP at 2.0 Å revealed structural similarity between TCTP H2-H3 helices and BAX H5-H6 helices. Site-directed mutagenesis of H2-H3 abolished TCTP's anti-apoptotic function. Crystal structure determination (2.0 Å), site-directed mutagenesis of TCTP, mitochondrial insertion assay, BAX dimerization inhibition assay Cell death and differentiation High 18274553
2018 Cytosolic BAX exists as an ensemble of conformers; distribution within this ensemble determines function. Crystal structure of BAX P168G mutant near the C-terminus and antibody 3C10 binding near the N-terminus both inhibit BAX by limiting exposure of membrane-associating helix α9, supporting an allosteric conformational ensemble model of BAX regulation. Crystal structure determination of BAX P168G and BAX-3C10 antibody complex, functional cytosolic BAX inhibition assays Structure High 30122452
2015 DRAM1 directly interacts with BAX, inhibits BAX autophagic degradation, recruits BAX to lysosomes, and thereby promotes BAX-mediated lysosomal cathepsin B release, tBID cleavage, and mitochondrial cytochrome c release. BAX at lysosomes thus initiates a lysosome-cathepsin B-tBID pathway leading to apoptosis. Co-immunoprecipitation, BAX protein stability assay, lysosomal fractionation, cathepsin B release assay, cytochrome c release assay Cell death & disease Medium 25633293

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Movement of Bax from the cytosol to mitochondria during apoptosis. The Journal of cell biology 1532 9382873
2018 BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis. Science (New York, N.Y.) 854 29472455
2017 Bax, Bak and beyond - mitochondrial performance in apoptosis. The FEBS journal 732 28755482
1997 Bax suppresses tumorigenesis and stimulates apoptosis in vivo. Nature 578 9024662
1998 Regulated targeting of BAX to mitochondria. The Journal of cell biology 535 9763432
2006 Role of Bax and Bak in mitochondrial morphogenesis. Nature 520 17035996
2011 Bcl-x(L) retrotranslocates Bax from the mitochondria into the cytosol. Cell 506 21458670
2009 Stepwise activation of BAX and BAK by tBID, BIM, and PUMA initiates mitochondrial apoptosis. Molecular cell 501 19917256
2003 Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis. The Journal of cell biology 496 12847083
2003 JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis. Neuron 434 12818176
2010 Molecular biology of Bax and Bak activation and action. Biochimica et biophysica acta 413 21195116
2003 p73 Induces apoptosis via PUMA transactivation and Bax mitochondrial translocation. The Journal of biological chemistry 308 14634023
2001 Prion protein protects human neurons against Bax-mediated apoptosis. The Journal of biological chemistry 289 11522774
1998 Bax involvement in p53-mediated neuronal cell death. The Journal of neuroscience : the official journal of the Society for Neuroscience 281 9454845
2007 Bax activation and mitochondrial insertion during apoptosis. Apoptosis : an international journal on programmed cell death 276 17453158
2002 Deficiency in Bak and Bax perturbs thymic selection and lymphoid homeostasis. Nature immunology 247 12244308
2016 Bax assembly into rings and arcs in apoptotic mitochondria is linked to membrane pores. The EMBO journal 242 26783362
2021 Physiological and pharmacological modulation of BAX. Trends in pharmacological sciences 237 34848097
2006 How do Bax and Bak lead to permeabilization of the outer mitochondrial membrane? Current opinion in cell biology 235 17046225
2008 Bid: a Bax-like BH3 protein. Oncogene 234 19641510
2006 Bcl-2 changes conformation to inhibit Bax oligomerization. The EMBO journal 220 16642033
2004 ASC is a Bax adaptor and regulates the p53-Bax mitochondrial apoptosis pathway. Nature cell biology 204 14730312
2007 The pathological role of Bax in cisplatin nephrotoxicity. Kidney international 196 17410096
2015 Direct Activation of Bax Protein for Cancer Therapy. Medicinal research reviews 187 26395559
2014 Structural model of active Bax at the membrane. Molecular cell 187 25458844
2007 Bnip3 mediates mitochondrial dysfunction and cell death through Bax and Bak. The Biochemical journal 181 17447897
2014 Mitochondrial shape governs BAX-induced membrane permeabilization and apoptosis. Molecular cell 173 25482509
2002 Bax and Bak independently promote cytochrome C release from mitochondria. The Journal of biological chemistry 170 11836241
2008 TCTP protects from apoptotic cell death by antagonizing bax function. Cell death and differentiation 167 18274553
1998 Bax. The pro-apoptotic Bcl-2 family member, Bax. The international journal of biochemistry & cell biology 159 9695020
2009 Molecular details of Bax activation, oligomerization, and membrane insertion. The Journal of biological chemistry 153 20008353
2018 VDAC2 enables BAX to mediate apoptosis and limit tumor development. Nature communications 152 30478310
2016 Bax and Bak Pores: Are We Closing the Circle? Trends in cell biology 152 27932064
2003 Mitochondrial membrane permeabilisation by Bax/Bak. Biochemical and biophysical research communications 146 12729579
2005 HSP60, Bax, apoptosis and the heart. Journal of cellular and molecular medicine 145 15784164
2012 Direct and selective small-molecule activation of proapoptotic BAX. Nature chemical biology 138 22634637
1997 Bax- and Bak-induced cell death in the fission yeast Schizosaccharomyces pombe. Molecular biology of the cell 137 9190211
2022 DRP1 interacts directly with BAX to induce its activation and apoptosis. The EMBO journal 122 35023587
2005 The RASSF1A tumor suppressor activates Bax via MOAP-1. The Journal of biological chemistry 120 16344548
2015 Inhibition of Pro-apoptotic BAX by a noncanonical interaction mechanism. Molecular cell 117 25684204
2016 Physiological and Pharmacological Control of BAK, BAX, and Beyond. Trends in cell biology 114 27498846
2002 BAX and BAK mediate p53-independent suppression of tumorigenesis. Cancer cell 109 12242152
2011 Bax: Addressed to kill. Biochimie 108 21641962
2000 BID-dependent and BID-independent pathways for BAX insertion into mitochondria. Cell death and differentiation 102 11139284
2018 Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy. The EMBO journal 94 30573668
2015 Bax-PGAM5L-Drp1 complex is required for intrinsic apoptosis execution. Oncotarget 91 26356820
2011 HDAC6 deacetylates Ku70 and regulates Ku70-Bax binding in neuroblastoma. Neoplasia (New York, N.Y.) 90 21847364
2010 BAX-dependent and BAX-independent regulation of Kiss1 neuron development in mice. Endocrinology 88 20926580
2019 Small-molecule allosteric inhibitors of BAX. Nature chemical biology 84 30718816
2018 Phosphorylation switches Bax from promoting to inhibiting apoptosis thereby increasing drug resistance. EMBO reports 83 29987135
2015 DRAM1 regulates apoptosis through increasing protein levels and lysosomal localization of BAX. Cell death & disease 83 25633293
2007 Bax-inhibiting peptides derived from Ku70 and cell-penetrating pentapeptides. Biochemical Society transactions 81 17635151
2009 Single-cell quantification of Bax activation and mathematical modelling suggest pore formation on minimal mitochondrial Bax accumulation. Cell death and differentiation 80 19745831
2019 Targeting BAX to drug death directly. Nature chemical biology 79 31209350
2009 Bax activation by Bim? Cell death and differentiation 79 19557009
2007 Cathepsin D-Bax death pathway in oxidative stressed neuroblastoma cells. Free radical biology & medicine 76 17395004
2004 Bax-inhibiting peptide derived from mouse and rat Ku70. Biochemical and biophysical research communications 76 15358121
2002 Bak and Bax function to limit adenovirus replication through apoptosis induction. Journal of virology 73 11932420
2007 BAX regulates follicular endowment in mice. Reproduction (Cambridge, England) 72 17616717
2016 An Autoinhibited Dimeric Form of BAX Regulates the BAX Activation Pathway. Molecular cell 71 27425408
2016 The porin VDAC2 is the mitochondrial platform for Bax retrotranslocation. Scientific reports 71 27620692
2014 BAX channel activity mediates lysosomal disruption linked to Parkinson disease. Autophagy 71 24686337
2010 Multistep and multitask Bax activation. Mitochondrion 68 20709625
2006 Androgen and its receptor promote Bax-mediated apoptosis. Molecular and cellular biology 68 16479009
2009 Hydrogen peroxide-induced Akt phosphorylation regulates Bax activation. Biochimie 67 19278624
2011 Bax inhibitor 1 in apoptosis and disease. Oncogene 65 21297665
2014 BCL2 and related prosurvival proteins require BAK1 and BAX to affect autophagy. Autophagy 64 24991825
2002 Bax, Bcl-2, and p53 expression in endometrial cancer. Gynecologic oncology 63 12217750
2017 Pore formation by dimeric Bak and Bax: an unusual pore? Philosophical transactions of the Royal Society of London. Series B, Biological sciences 60 28630157
2007 Protein kinase Czeta abrogates the proapoptotic function of Bax through phosphorylation. The Journal of biological chemistry 60 17525161
2013 Consequences of the combined loss of BOK and BAK or BOK and BAX. Cell death & disease 59 23744350
2024 Lipid unsaturation promotes BAX and BAK pore activity during apoptosis. Nature communications 56 38830851
2012 Structural mechanism of Bax inhibition by cytomegalovirus protein vMIA. Proceedings of the National Academy of Sciences of the United States of America 56 23213219
2014 Activation of Bax in three models of retinitis pigmentosa. Investigative ophthalmology & visual science 54 24825107
2006 Decreased expression of tumour suppressor Bax-interacting factor-1 (Bif-1), a Bax activator, in gastric carcinomas. Pathology 54 16916719
2021 Eltrombopag directly inhibits BAX and prevents cell death. Nature communications 50 33602934
2022 BAX and BAK dynamics control mitochondrial DNA release during apoptosis. Cell death and differentiation 49 35347233
2008 Apoptosis: Stabbed in the BAX. Nature 49 18948940
2017 Apoptotic foci at mitochondria: in and around Bax pores. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 48 28630156
2004 Bax translocation and mitochondrial fragmentation induced by Helicobacter pylori. Gut 47 15138206
2019 Completion of BAX recruitment correlates with mitochondrial fission during apoptosis. Scientific reports 46 31719602
2015 Regulation of Bax/mitochondria interaction by AKT. FEBS letters 45 26763134
2015 Bax regulates neuronal Ca2+ homeostasis. The Journal of neuroscience : the official journal of the Society for Neuroscience 44 25632145
2010 Prostaglandins antagonistically control Bax activation during apoptosis. Cell death and differentiation 43 20966963
2008 Higher expression of Bax in regulatory T cells increases vascular inflammation. Frontiers in bioscience : a journal and virtual library 43 18508723
2002 Cell death, Bcl-2, Bax, and the cerebellum. Cerebellum (London, England) 43 12879966
2023 Mitophagy restricts BAX/BAK-independent, Parkin-mediated apoptosis. Science advances 41 37224250
2018 Ensemble Properties of Bax Determine Its Function. Structure (London, England : 1993) 41 30122452
2009 Bax activates endophilin B1 oligomerization and lipid membrane vesiculation. The Journal of biological chemistry 41 19805544
2000 Characterization of Bax-sigma, a cell death-inducing isoform of Bax. Biochemical and biophysical research communications 40 10772918
2020 BAX inhibitor-1: between stress and survival. The FEBS journal 39 31841271
2017 Allosteric sensitization of proapoptotic BAX. Nature chemical biology 39 28692068
2019 Pharmacological inhibition of Bax-induced cell death: Bax-inhibiting peptides and small compounds inhibiting Bax. Experimental biology and medicine (Maywood, N.J.) 38 30836793
2011 Bid and Bax are involved in granulosa cell apoptosis during follicular atresia in porcine ovaries. The Journal of reproduction and development 38 21441714
2008 Cholesterol effects on BAX pore activation. Journal of molecular biology 38 18590739
2008 Mitochondria potential, bax "activation," and programmed cell death. Methods in molecular biology (Clifton, N.J.) 37 18175815
2012 A BAX/BAK and cyclophilin D-independent intrinsic apoptosis pathway. PloS one 35 22719850
2006 Expression of the Bax inhibitor-1 gene in pulmonary adenocarcinoma. Cancer 34 16353209
2019 Mitochondrial translocation of cyclin C stimulates intrinsic apoptosis through Bax recruitment. EMBO reports 32 31385392
2008 Bax shuttling after neonatal hypoxia-ischemia: hyperoxia effects. Journal of neuroscience research 32 18655197

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