{"gene":"BAK1","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2001,"finding":"BAK (together with BAX) is an essential gateway for mitochondrial dysfunction during apoptosis: tBID triggers BAK homooligomerization at mitochondria, causing cytochrome c release; cells lacking both BAX and BAK are completely resistant to tBID-induced cytochrome c release and multiple apoptotic stimuli (staurosporine, UV, growth factor deprivation, etoposide, ER stress agents).","method":"Genetic double-knockout (Bax-/- Bak-/- mouse embryonic fibroblasts), cytochrome c release assay, apoptosis assays with multiple stimuli","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with multiple orthogonal stimuli and cytochrome c release assay; replicated across multiple death signals in a landmark study","pmids":["11326099"],"is_preprint":false},{"year":2003,"finding":"In viable cells, BAK is maintained in an inactive monomeric conformation at the mitochondrial outer membrane by direct interaction with VDAC2 (but not VDAC1). VDAC2 specifically binds the inactive conformer of BAK; death signals (e.g., tBID, BIM, BAD) displace VDAC2 from BAK, enabling BAK homo-oligomerization and apoptosis. VDAC2 deficiency enhances BAK oligomerization and apoptosis susceptibility; VDAC2 overexpression prevents BAK activation.","method":"Co-immunoprecipitation, VDAC2-knockout and overexpression cells, BAK oligomerization assays, apoptosis assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic KO, and overexpression with multiple orthogonal readouts in a single rigorous study","pmids":["12881569"],"is_preprint":false},{"year":2004,"finding":"Mitochondria-localized p53 directly interacts with BAK, causing BAK oligomerization and cytochrome c release. Formation of the p53-BAK complex coincides with loss of the BAK-MCL1 interaction, suggesting p53 displaces MCL1 to activate BAK.","method":"Co-immunoprecipitation, cytochrome c release assay, mitochondrial fractionation","journal":"Nature Cell Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and functional cytochrome c release assay in a single lab study","pmids":["15077116"],"is_preprint":false},{"year":2003,"finding":"BAK (and BAX) can localize to the endoplasmic reticulum in addition to mitochondria. ER-targeted BAK causes progressive ER Ca2+ depletion and caspase-12 cleavage, demonstrating a distinct ER-based apoptotic pathway separable from the mitochondrial pathway.","method":"Subcellular targeting constructs, fractionation, Ca2+ measurements, caspase cleavage assays in Bax-/-Bak-/- cells reconstituted with compartment-targeted mutants","journal":"Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic background (DKO cells), organelle-targeted mutants, multiple orthogonal readouts (Ca2+, caspase cleavage, cytochrome c)","pmids":["12847083"],"is_preprint":false},{"year":2007,"finding":"BAK uniquely interacts with mitofusins MFN1 and MFN2 at the mitochondrial outer membrane. During apoptosis, BAK dissociates from MFN2 and enhances association with MFN1; BH3-domain mutation prevents MFN2 dissociation and diminishes BAK's mitochondrial fragmentation activity. BAK (but not BAX) drives mitochondrial fragmentation during apoptosis.","method":"Co-immunoprecipitation, Bak-deficient MEFs and primary neurons, reconstitution in DKO cells, BH3 domain mutagenesis, mitochondrial morphology imaging","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, genetic KO in multiple cell types, mutagenesis, and reconstitution with multiple orthogonal readouts","pmids":["17606912"],"is_preprint":false},{"year":2013,"finding":"BID BH3 helix activates BAK by engaging the canonical BH3-binding groove (activation site) of BAK via a 'hit-and-run' mechanism: BID binds transiently, then dissociates, allowing BAK oligomerization at the same overlapping interface. BAK BH1 groove mutation prevents MOMP but not BID binding; BAK BH3 mutations allow BID binding and activation but block oligomerization. BH3-only proteins NOXA and BAD do not activate BAK.","method":"NMR solution structure of BID BH3-BAK complex, site-directed mutagenesis, liposomal cytochrome c release assay, MOMP assay","journal":"Nature Structural & Molecular Biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure combined with mutagenesis and functional in vitro reconstitution in a single rigorous study","pmids":["23604079"],"is_preprint":false},{"year":2013,"finding":"Full-length BAK resides constitutively at the outer mitochondrial membrane and requires direct BH3 ligand interaction at its canonical BH3-binding groove (not the α1/α6 site used by BAX) to be activated and release cytochrome c. Photoreactive BH3 crosslinking mapped the BAK trigger site to the BH3-binding pocket, distinct from the BAX α1/α6 trigger site.","method":"In vitro reconstitution with purified full-length BAK, liposomal release assay, photoreactive BH3 crosslinking, mutagenesis-based solubilization","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution, photocrosslinking, and mutagenesis in a single study establishing distinct BAK vs BAX activation sites","pmids":["23404709"],"is_preprint":false},{"year":2014,"finding":"BAK undergoes conformational separation of core and latch domains upon activation by specific BH3 peptides, analogous to BAX. Crystal structure of the BAK core domain dimer reveals the symmetric homodimer as a key intermediate in pore-forming oligomer assembly.","method":"Crystal structure of BAK core domain dimer, crosslinking experiments, BH3 peptide activation assays","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with crosslinking and functional activation assays","pmids":["25175025"],"is_preprint":false},{"year":2018,"finding":"After BAK/BAX activation and cytochrome c release during apoptosis, large BAK/BAX macropores appear in the mitochondrial outer membrane, allowing the inner mitochondrial membrane to herniate into the cytosol and carry mitochondrial matrix contents including mtDNA, thereby enabling cGAS/STING activation.","method":"Live-cell lattice light-sheet microscopy in mouse embryonic fibroblasts, caspase inhibition experiments","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct live-cell visualization with lattice light-sheet microscopy, mechanistic link to innate immune signaling established","pmids":["29472455"],"is_preprint":false},{"year":2022,"finding":"BAK and BAX present distinct oligomerization properties: BAK organizes into smaller structures with faster kinetics than BAX. BAK recruits and accelerates BAX assembly into oligomers, and both co-assemble into the same apoptotic pores. The relative availability of BAX and BAK determines apoptotic pore growth rate and kinetics of mtDNA release, with consequences for cGAS/STING activation.","method":"Single-molecule imaging, super-resolution microscopy, kinetic analysis of oligomerization, pore visualization, cGAS/STING pathway assays","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biophysical and cell biological methods establishing distinct kinetics and cooperative assembly","pmids":["35120587"],"is_preprint":false},{"year":2017,"finding":"Disordered clusters of BAK dimers (not ordered oligomers) generate lipidic pores in the mitochondrial outer membrane. Cysteine labeling and linkage analysis across full-length BAK showed the N-terminus is mobile and solvent-exposed post-activation, while dimer-dimer interactions are more labile than BH3:groove interactions within dimers. Mathematical simulations support a disordered dimer-cluster pore model.","method":"Cysteine labeling, disulfide crosslinking, mathematical simulations of dimer arrangement","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — comprehensive cysteine-scanning crosslinking across full-length BAK combined with quantitative modeling","pmids":["28182867"],"is_preprint":false},{"year":2020,"finding":"Crystal structures of human BAK core domain dimers reveal preferred binding sites for membrane lipids and detergents on the dimer surface. Phospholipid headgroup and one acyl chain (sn2) associate with one core dimer while the other acyl chain (sn1) associates with a neighboring dimer, suggesting lipids bridge BAK dimers to promote oligomerization, unlike typical protein-protein interfaces.","method":"Crystal structures of BAK core domain dimers, lipid-binding analysis","journal":"Nature Structural & Molecular Biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with lipid-binding sites identified, providing structural mechanism for lipid-mediated oligomerization","pmids":["32929280"],"is_preprint":false},{"year":2021,"finding":"Hydrogen-deuterium exchange mass spectrometry of membrane-bound BAK revealed that the BH4 domain maintains the inactive conformation of BAK; disrupting the BH4 domain is sufficient for constitutive BAK activation. The entire N-terminal region preceding BAK oligomerization domains becomes disordered post-activation and remains disordered in the activated oligomer. Removal of the disordered N-terminus slightly potentiates BAK-mediated membrane permeabilization.","method":"HDX-MS on membrane-bound BAK (liposomes with mitochondrial lipids), site-directed mutagenesis, liposomal and mitochondrial permeabilization assays","journal":"EMBO Journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — HDX-MS structural analysis combined with mutagenesis and functional reconstitution, single lab but multiple orthogonal methods","pmids":["34523147"],"is_preprint":false},{"year":2018,"finding":"During mitophagy, Parkin directly ubiquitinates BAK at a conserved lysine in its hydrophobic groove (critical for BH3-only protein activation and homo-dimerization), inhibiting BAK activation and lethal oligomer formation. BAK-dependent MOMP during apoptosis also promotes PINK1-dependent Parkin activation, creating a feedback loop.","method":"In vitro ubiquitination assay, Co-IP, BAK activation assay, mitophagy induction, mutagenesis of ubiquitination site","journal":"EMBO Journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro ubiquitination reconstitution, site-specific mutagenesis, and functional BAK activity assays with multiple orthogonal methods","pmids":["30573668"],"is_preprint":false},{"year":2012,"finding":"Vitamin K2 (menaquinone) covalently binds to BAK at cysteine-166, inducing BAK oligomerization and BAK-dependent cytochrome c release and apoptosis. This effect is specific to BAK and does not require BAX; VK2-2,3-epoxide (intracellular metabolite) mediates the covalent attachment.","method":"Pulldown/binding assay, site-directed mutagenesis (C166), cytochrome c release assay, BAK-specific siRNA knockdown","journal":"Molecular Pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding with mutagenesis identifying covalent modification site, functional validation with siRNA, single lab","pmids":["23229512"],"is_preprint":false},{"year":2020,"finding":"Neural-specific splicing of the evolutionarily conserved Bak1 microexon 5 (regulated by PTBP1 downregulation during neuronal development) triggers nonsense-mediated mRNA decay of Bak1 transcripts, suppressing pro-apoptotic BAK1 protein expression in neurons. Germline heterozygous ablation of exon 5 increases BAK1 protein exclusively in the brain, increases neuronal apoptosis, and causes early postnatal mortality.","method":"Alternative splicing analysis, PTBP1 knockdown/knockout, NMD assays, germline exon 5 knockout mice, neuronal apoptosis quantification","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic model with multiple orthogonal methods (splicing, NMD, KO mice, apoptosis quantification) establishing a neural-specific regulatory mechanism","pmids":["32710818"],"is_preprint":false},{"year":2017,"finding":"The VDAC2-BAK axis regulates peroxisomal membrane permeability. Loss of VDAC2 shifts BAK localization from mitochondria to peroxisomes, causing peroxisomal deficiency. Peroxisome-targeted BAK causes release of peroxisomal matrix proteins to the cytosol; BAK activators PUMA and BIM permeabilize peroxisomes in a BAK-dependent manner.","method":"Subcellular fractionation, peroxisome-targeted BAK constructs, BAK knockdown, overexpression of VDAC2/BCL-XL/MCL-1","journal":"Journal of Cell Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — organelle-targeted constructs and genetic KD with functional peroxisomal permeability readout, single lab","pmids":["28174205"],"is_preprint":false},{"year":2016,"finding":"Bcl-xL physiologically restrains BAK by direct physical interaction via BAK's BH3:groove interface. A BAK Q75L (mouse)/Q77L (human) mutation specifically disrupts BAK-BCL-XL binding without affecting BAK structure or killing activity, reducing affinity through loss of a single hydrogen bond. In vivo, loss of BCL-XL binding to BAK causes significant defects in T-cell and platelet survival.","method":"Site-directed mutagenesis, binding affinity measurements, knockin mouse model, T-cell and platelet survival analysis","journal":"Genes & Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — precision mutagenesis with in vitro affinity measurement and in vivo knockin mouse validation","pmids":["27198225"],"is_preprint":false},{"year":2024,"finding":"Unsaturated lipids enriched in the proximal membrane environment of BAK promote BAX pore activity. Lipidomics of BAK isolated in lipid nanodiscs shows enrichment of unsaturated species near BAK during apoptosis. The fatty acid desaturase FADS2 enhances apoptosis sensitivity and cGAS/STING activation downstream of mtDNA release.","method":"Comparative lipidomics (lipid nanodisc isolation of BAK), model membrane pore assays, isolated mitochondria assays, molecular dynamics simulations, FADS2 manipulation","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — lipidomics, in vitro reconstitution, MD simulations, and cellular validation in a single study with multiple orthogonal methods","pmids":["38830851"],"is_preprint":false},{"year":2013,"finding":"BAK and BAX form stable protein-permeable pores of tunable, dynamic size in lipid membranes. Single-vesicle imaging showed cBid-activated BAK (BakΔC21) forms pores large enough to release not only cytochrome c but also 104 kDa allophycocyanin. Pore area evolves with time and protein concentration but not cardiolipin concentration, consistent with proteolipidic pore nature.","method":"Single-vesicle fluorescence assay, size-exclusion analysis, protein concentration titration, cardiolipin manipulation","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution at single-vesicle level with systematic mechanistic dissection","pmids":["24100034"],"is_preprint":false},{"year":2013,"finding":"Myc-induced AMPK activation stabilizes p53 via Ser15 phosphorylation, leading to mitochondrial p53 accumulation. Mitochondrial p53 interacts with the BAK-BCL-XL complex, inducing BAK conformational activation without disrupting the BAK-BCL-XL interaction. Subsequent release of activated BAK from this complex leads to spontaneous BAK oligomerization and apoptosis.","method":"Co-immunoprecipitation, BAK conformational activation assay, AMPK inhibition, p53 knockdown, mitochondrial fractionation","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and conformational activation assays, single lab, multiple pathway manipulations","pmids":["23589839"],"is_preprint":false},{"year":2024,"finding":"Endogenous BAK is recruited to apoptotic pores before BAX. Both BAK and BAX together form unordered mosaic rings on the mitochondrial outer membrane in wild-type cells. In single-knockout cells, either protein alone can form rings independently. Overexpression of BAK produces novel structures absent in non-overexpressing apoptotic cells.","method":"Live- and fixed-cell STED super-resolution microscopy in wild-type, BAX-KO, and BAK-KO cells and human primary cells","journal":"Cell Death and Differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct super-resolution imaging in endogenous-expression conditions and multiple genetic backgrounds","pmids":["38503846"],"is_preprint":false},{"year":2007,"finding":"In Arabidopsis, BAK1 (SERK3) forms a ligand-dependent complex with the immune receptor FLS2 within minutes of flagellin stimulation. BAK1 positively regulates early and late flagellin-triggered immune responses (including FLS2 and EFR signaling) independently of its role in brassinosteroid signaling.","method":"Co-immunoprecipitation in planta (ligand-dependent), bak1 mutant analysis, flagellin response assays, brassinosteroid sensitivity controls","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo Co-IP with ligand-dependence established, genetic mutant analysis, and multiple response readouts; replicated by independent lab in PMID:17626179","pmids":["17625569","17626179"],"is_preprint":false},{"year":2002,"finding":"Arabidopsis BAK1 was identified as a specific interactor of BRI1 (brassinosteroid receptor) by yeast two-hybrid. BAK1/BRI1 interaction activates their kinase activities through transphosphorylation in yeast. BAK1 and BRI1 share subcellular localization and physically associate in plants. BAK1 overexpression phenocopies BRI1 overexpression; bak1 knockout gives a weak bri1-like phenotype.","method":"Yeast two-hybrid, co-immunoprecipitation in plants, overexpression/knockout genetic analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid plus in planta Co-IP plus reciprocal genetic overexpression and knockout phenotypes; landmark study","pmids":["12150928"],"is_preprint":false},{"year":2008,"finding":"BRI1 transphosphorylates BAK1 in vitro on specific kinase-domain residues critical for BAK1 function; BR-dependent BRI1 activation precedes BAK1 association in planta. BAK1 subsequently transphosphorylates BRI1, quantitatively increasing BRI1 kinase activity. A sequential transphosphorylation model is proposed: BRI1 controls signaling specificity, then activates BAK1 via transphosphorylation, and BAK1 reciprocally enhances BRI1.","method":"In vitro kinase assay with phosphosite mapping (mass spectrometry), in planta phosphorylation analysis, temporal dissection of BR signaling","journal":"Developmental Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase reconstitution with phosphosite identification by MS and in planta validation","pmids":["18694562"],"is_preprint":false},{"year":2014,"finding":"BIR2, a novel BAK1-interacting receptor-like kinase (identified by LC/ESI-MS/MS), is unidirectionally phosphorylated by BAK1. BIR2 constitutively interacts with BAK1, preventing BAK1-FLS2 complex formation in the absence of ligand. PAMP perception triggers BIR2 release from BAK1, enabling BAK1 recruitment to the FLS2 complex. BIR2 acts as a negative regulator of PAMP-triggered immunity.","method":"LC/ESI-MS/MS interactome, Co-immunoprecipitation, bir2 mutant phenotyping, phosphorylation assays","journal":"Current Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS-based interactome identification, reciprocal Co-IP, genetic mutant, and phosphorylation assays with multiple orthogonal methods","pmids":["24388849"],"is_preprint":false},{"year":2014,"finding":"Protein phosphatase 2A (PP2A), composed of subunits A1, C4, and B'η/ζ, constitutively associates with BAK1 in planta and dephosphorylates BAK1 to negatively regulate plant innate immunity. Impairment of PP2A-BAK1 interaction increases steady-state BAK1 phosphorylation and potentiates immune responses.","method":"Co-immunoprecipitation, PP2A mutant analysis, phosphorylation assays, immune response measurements","journal":"EMBO Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and phosphorylation analysis with genetic validation, single lab study","pmids":["25085430"],"is_preprint":false},{"year":2019,"finding":"BAK1 directly interacts with and phosphorylates CNGC20 (a Ca2+-permeable channel) at specific sites in its C-terminal cytosolic domain, regulating CNGC20 protein stability and Ca2+ channel function. This BAK1-CNGC20 axis controls cellular Ca2+ homeostasis to contain cell death in Arabidopsis.","method":"RNAi genetic screen, Co-IP, in vitro kinase/phosphorylation assay, electrophysiology, genetic epistasis","journal":"Current Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro phosphorylation assay and Co-IP with genetic validation, single lab","pmids":["31679931"],"is_preprint":false},{"year":2019,"finding":"BAK1 undergoes Ca2+-dependent proteolytic cleavage at a surface-exposed Asp287 residue, conserved in Arabidopsis, N. benthamiana, and yeast. This cleavage is regulated by developmental cues and immune stimulation. The BAK1 D287A mutation impairs BAK1 phosphorylation of its substrate BIK1, plasma membrane localization, and BAK1 function in immunity, BR signaling, and cell death containment.","method":"Site-directed mutagenesis (D287A), in planta phosphorylation assays, plasma membrane localization imaging, genetic complementation","journal":"Plant Physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with multiple functional readouts across three organisms, single lab","pmids":["30782965"],"is_preprint":false},{"year":2015,"finding":"RLP23 forms a constitutive, ligand-independent complex with SOBIR1, and upon nlp20 (NLP peptide) binding, recruits BAK1 into a tripartite RLP23-SOBIR1-BAK1 complex to activate immune responses.","method":"Co-immunoprecipitation in planta, nlp20 binding assay, genetic mutant analysis","journal":"Nature Plants","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo Co-IP and ligand-dependent complex formation, single lab","pmids":["27251392"],"is_preprint":false},{"year":2019,"finding":"The lectin receptor kinase LecRK-VI.2 constitutively associates with BAK1 in vivo, and both LecRK-VI.2 and BAK1 kinase activities are required for eNAD+/eNADP+ signaling and systemic acquired resistance (SAR) in Arabidopsis.","method":"Co-immunoprecipitation in planta, kinase-dead mutant analysis, SAR assays","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo Co-IP and kinase-dead mutant with functional SAR assay, single lab","pmids":["31641112"],"is_preprint":false},{"year":2020,"finding":"BAK1 phosphorylates the plasma membrane H+-ATPase AHA2 at T858 and T881 in its C-terminal domain, enhancing H+ pump activity and promoting K+ uptake under low-potassium stress. BAK1 directly interacts with the AHA2 C-terminus.","method":"Co-IP, in vitro kinase assay with phosphosite identification, aha2 and bak1 mutant analysis, phosphorylation-mimic mutants","journal":"Plant Physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay with phosphosite mapping and genetic validation with phosphomimetic mutants, single lab","pmids":["35604103"],"is_preprint":false},{"year":2024,"finding":"EFR can allosterically activate BAK1 kinase activity via a non-catalytic mechanism: a kinase-dead EFR variant retains ability to enhance BAK1 catalytic activity. HDX-MS analysis and suppressor mutagenesis indicate EFR must adopt its active conformation to allosterically activate BAK1 by supporting αC-helix positioning. BAK1 first phosphorylates EFR in the activation loop to stabilize EFR's active conformation, allowing EFR to then allosterically activate BAK1.","method":"HDX-MS, kinase-dead mutant analysis, homology-based intragenic suppressor mutagenesis, in vitro kinase assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Moderate — HDX-MS structural analysis, mutagenesis, and in vitro kinase reconstitution establishing non-catalytic allosteric activation mechanism","pmids":["39028038"],"is_preprint":false},{"year":2020,"finding":"BAK1 is phosphorylated by and interacts with all three Arabidopsis catalases (CAT1, CAT2, CAT3), identified by affinity purification/LC-MS/MS. BAK1-mediated catalase phosphorylation enhances catalase activity and reduces H2O2 accumulation under high light, regulating plant growth. BAK1 overexpression effect on high-light growth is abolished in triple catalase knockout plants.","method":"Affinity purification/LC-MS/MS, in vitro kinase assay with phosphosite mapping, genetic analysis (bak1 and cat mutants)","journal":"International Journal of Molecular Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction, in vitro phosphorylation, and genetic validation, single lab","pmids":["32093294"],"is_preprint":false},{"year":2019,"finding":"The receptor-like kinase NIK1 negatively regulates FLS2/BAK1 complex formation. NIK1 interacts with both FLS2 and BAK1; this interaction is enhanced upon flg22 perception. NIK1 acts as a negative regulator of antibacterial PTI while positively regulating antiviral immunity.","method":"Co-immunoprecipitation, NIK1 overexpression/knockout, PTI response assays, bacterial resistance assays","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo Co-IP with ligand-dependent enhancement and genetic analysis, single lab","pmids":["31676803"],"is_preprint":false},{"year":2020,"finding":"Cell death in bak1 bkk1 double mutants is suppressed by mutation of the NLR helper proteins ADR1s, indicating BAK1 depletion triggers NLR-dependent ETI-like cell death. Pseudomonas effector HopB1, which proteolytically cleaves activated BAK1, triggers cell death in an ADR1-dependent manner, suggesting BAK1 and its paralogs are guarded by NLRs.","method":"Genetic epistasis (bak1 bkk1 adr1 triple mutants), HopB1 expression/delivery, protease activity analysis","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with NLR mutants and bacterial effector delivery, single lab","pmids":["33055218"],"is_preprint":false},{"year":2016,"finding":"BAK1 and BKK1-mediated cell death control requires nucleocytoplasmic trafficking; loss-of-function of nucleoporin NUP85-like gene SBB1 (and other nucleoporins in the same sub-complex) or DEAD-box RNA helicase DRH1 suppresses bak1 bkk1 cell death. Suppression correlates with blocked poly(A)+ RNA export and reduced salicylic acid accumulation.","method":"Genetic suppressor screen, epistasis analysis, mRNA export assays, salicylic acid measurements","journal":"Plant Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis from suppressor screen with mRNA export and SA mechanistic readouts, single lab","pmids":["26775605"],"is_preprint":false},{"year":2019,"finding":"Kinase activity of both SOBIR1 and BAK1 is required for SOBIR1-induced constitutive immunity and SOBIR1 phosphorylation in planta. BAK1 kinase activity is essential for the defense response triggered by the tomato LRR-RLP Cf-4. SOBIR1 and BAK1 likely transphosphorylate each other within the signaling-competent receptor complex.","method":"Kinase-dead mutant analysis, phosphorylation assays, gene silencing, co-immunoprecipitation, live cell imaging","journal":"Molecular Plant Pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase-dead mutants with phosphorylation and functional assays, multiple orthogonal methods, single lab","pmids":["30407725"],"is_preprint":false},{"year":2024,"finding":"Crystal structure of MIK2-SCOOP-BAK1 complex reveals that SCOOPs use their SxS motif to bind MIK2 and carboxy-terminal GGR residues to bridge MIK2 to BAK1. Specific N-glycans on MIK2 directly interact with BAK1 upon SCOOP sensing; loss of this N-glycosylation site does not affect MIK2 localization or conformation but markedly reduces MIK2-BAK1 affinity and abolishes SCOOP-triggered immunity.","method":"Crystal structure of ternary complex, N-glycosylation mutagenesis, binding affinity measurements, genetic complementation","journal":"Nature Plants","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis, binding measurements, and in planta functional validation","pmids":["39511418"],"is_preprint":false},{"year":2017,"finding":"BAK1-dependent PTI contributes to antiviral resistance in Arabidopsis; bak1 mutants show increased susceptibility to three RNA viruses. Crude viral extracts (but not purified virions) induce PTI marker responses in a BAK1-dependent manner.","method":"bak1 mutant viral infection assays, PTI marker response assays with viral extracts vs purified virions","journal":"Molecular Plant-Microbe Interactions","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mutant analysis with multiple viruses and functional PTI readouts, single lab","pmids":["23902263"],"is_preprint":false},{"year":2017,"finding":"BAK1 is involved in AtRALF1-induced inhibition of root cell expansion. AtRALF1 physically interacts with BAK1 (Kd = 4.6 μM), induces BAK1 phosphorylation, and requires BAK1 for induction of AtRALF1-responsive genes. Binding to intact seedlings is partly BAK1-dependent.","method":"Binding affinity measurement (acridinium-labeled peptide), Co-IP, bak1 mutant analysis, phosphorylation assay, gene expression analysis","journal":"PLoS Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay with Kd measurement, phosphorylation evidence, and genetic validation, single lab","pmids":["29028796"],"is_preprint":false},{"year":2013,"finding":"Visualization by FLIM in live Arabidopsis root epidermal cells showed BR signaling activation increases BAK1-BRI1 heterooligomerization by ~50% at the plasma membrane. Approximately 7% of the BRI1 PM pool constitutively heterooligomerizes with BAK1 independent of BR ligand.","method":"Comparative colocalization analysis and FLIM (fluorescence lifetime imaging microscopy) in live plant cells","journal":"Plant Physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct live-cell FLIM imaging quantifying receptor heterooligomerization, single lab","pmids":["23796795"],"is_preprint":false}],"current_model":"BAK1 (human/mammalian BAK) is a proapoptotic BCL-2 family multidomain protein constitutively localized to the mitochondrial outer membrane (restrained in inactive monomer form by VDAC2 and BCL-XL), which upon activation by direct BH3-only protein binding at its canonical BH3-binding groove undergoes conformational separation of core and latch domains, forms symmetric homodimers that assemble into disordered clusters bridged partly by membrane lipids (especially unsaturated species), and generates proteolipidic macropores that release cytochrome c, Smac/DIABLO, and ultimately mitochondrial DNA to activate cGAS/STING-dependent innate immunity; BAK activation is negatively regulated by VDAC2 binding, BCL-XL restraint, Parkin-mediated ubiquitination of its hydrophobic groove, and neural-specific NMD of its mRNA via PTBP1-regulated microexon splicing; BAK also permeabilizes ER and peroxisomal membranes and regulates mitochondrial morphology by interacting with mitofusins, while the plant ortholog/namesake BAK1 (BRI1-ASSOCIATED RECEPTOR KINASE 1) is an LRR-receptor-like kinase coreceptor that transphosphorylates ligand-binding receptor kinases (BRI1, FLS2, EFR, MIK2) and is itself regulated by PP2A dephosphorylation, BIR2-mediated sequestration, proteolytic cleavage at D287, and allosteric activation by its partner receptors."},"narrative":{"mechanistic_narrative":"The symbol BAK1 in this timeline maps to two entirely distinct, unrelated proteins that share only a name: mammalian BAK, a proapoptotic BCL-2 family pore-forming protein, and Arabidopsis BAK1 (SERK3), a plant leucine-rich-repeat receptor-like kinase coreceptor. Because both are internally coherent and supported by High-confidence evidence, each is summarized in turn. Mammalian BAK is an essential effector of mitochondrial outer membrane permeabilization (MOMP) during apoptosis: together with BAX it forms the indispensable gateway whose loss renders cells resistant to diverse death stimuli [PMID:11326099]. In viable cells BAK is held in an inactive monomeric conformation at the mitochondrial outer membrane through direct binding by VDAC2 and BCL-XL, with the BH4 domain stabilizing the latent state [PMID:12881569, PMID:34523147, PMID:27198225]. Activation requires transient \"hit-and-run\" engagement of the canonical BH3-binding groove by BH3-only ligands such as BID, a trigger site distinct from the BAX α1/α6 site [PMID:23604079, PMID:23404709]; this drives separation of the core and latch domains and assembly of symmetric core-domain homodimers [PMID:25175025]. Dimers coalesce into disordered clusters bridged in part by membrane lipids—particularly unsaturated species—to generate dynamically sized proteolipidic macropores that release cytochrome c and larger matrix contents [PMID:28182867, PMID:32929280, PMID:38830851, PMID:24100034]. These macropores permit inner-membrane herniation and mtDNA release that activates cGAS/STING innate immunity, with BAK recruited ahead of BAX and accelerating its co-assembly into shared apoptotic pores [PMID:29472455, PMID:35120587, PMID:38503846]. BAK also permeabilizes ER and peroxisomal membranes and remodels mitochondrial morphology via mitofusin interactions [PMID:12847083, PMID:28174205, PMID:17606912], and is negatively regulated by Parkin-mediated ubiquitination of its groove and by neural-specific NMD of its transcript [PMID:30573668, PMID:32710818]. In contrast, plant BAK1 is a coreceptor LRR-kinase that transphosphorylates and is reciprocally activated by ligand-binding receptor kinases including BRI1 in brassinosteroid signaling and FLS2/EFR/MIK2 in pattern-triggered immunity [PMID:12150928, PMID:18694562, PMID:17625569, PMID:17626179, PMID:39511418, PMID:39028038]. This dual occupancy of one symbol reflects nomenclatural collision rather than a single biological entity.","teleology":[{"year":2001,"claim":"Established that BAK, redundantly with BAX, is the obligatory effector gateway for mitochondrial apoptosis, defining the genetic requirement for cytochrome c release.","evidence":"Bax-/- Bak-/- MEFs challenged with multiple death stimuli and cytochrome c release assays","pmids":["11326099"],"confidence":"High","gaps":["Did not resolve the molecular conformational steps of BAK activation","Relative contributions of BAK vs BAX not separated"]},{"year":2003,"claim":"Identified VDAC2 as the direct restraint that keeps inactive BAK monomeric, explaining how BAK is held in check in viable cells.","evidence":"Reciprocal Co-IP, VDAC2 KO and overexpression, BAK oligomerization and apoptosis readouts","pmids":["12881569"],"confidence":"High","gaps":["Structural basis of VDAC2 selectivity for inactive BAK not defined","How death signals displace VDAC2 mechanistically not resolved"]},{"year":2003,"claim":"Showed BAK function extends beyond mitochondria to the ER, defining a Ca2+-dependent ER apoptotic pathway.","evidence":"Compartment-targeted BAK constructs in DKO cells with Ca2+ and caspase-12 readouts","pmids":["12847083"],"confidence":"High","gaps":["Endogenous contribution of ER-localized BAK versus mitochondrial pool unclear"]},{"year":2004,"claim":"Linked the p53 tumor suppressor directly to BAK activation, providing a transcription-independent route to MOMP.","evidence":"Co-IP and cytochrome c release with mitochondrial fractionation","pmids":["15077116"],"confidence":"Medium","gaps":["Single-lab Co-IP; whether p53 directly activates or displaces MCL1 not disentangled","Stoichiometry and affinity of p53-BAK not measured"]},{"year":2007,"claim":"Distinguished BAK from BAX by its mitofusin interactions controlling mitochondrial fragmentation during apoptosis.","evidence":"Co-IP, Bak-deficient MEFs/neurons, BH3 mutagenesis, morphology imaging","pmids":["17606912"],"confidence":"High","gaps":["Mechanistic coupling of MFN switching to pore formation not established"]},{"year":2013,"claim":"Resolved the activation trigger site, showing BH3-only ligands engage BAK's canonical groove via a transient hit-and-run mechanism distinct from the BAX trigger site.","evidence":"NMR of BID BH3-BAK, photoreactive crosslinking, mutagenesis, liposomal release assays","pmids":["23604079","23404709"],"confidence":"High","gaps":["How transient ligand binding is converted to stable oligomer not fully detailed","Which endogenous BH3-only proteins dominate in different cell types unclear"]},{"year":2013,"claim":"Characterized BAK pores as protein-permeable structures of tunable size, defining their proteolipidic nature.","evidence":"Single-vesicle fluorescence with size-exclusion and concentration/cardiolipin titration","pmids":["24100034"],"confidence":"High","gaps":["Native pore geometry in intact mitochondria not directly imaged here"]},{"year":2014,"claim":"Defined the symmetric core-domain homodimer and core/latch separation as the structural intermediate of pore assembly.","evidence":"Crystal structure of BAK core dimer with crosslinking and BH3 activation","pmids":["25175025"],"confidence":"High","gaps":["How dimers assemble into higher-order pores not resolved by static structure"]},{"year":2016,"claim":"Demonstrated BCL-XL restrains BAK in vivo through the BH3:groove interface, with physiological consequences for lymphocyte and platelet survival.","evidence":"Precision Q75L/Q77L mutagenesis, affinity measurement, knockin mice","pmids":["27198225"],"confidence":"High","gaps":["Relative weighting of BCL-XL versus VDAC2 restraint in different tissues not quantified"]},{"year":2017,"claim":"Revealed the disordered dimer-cluster architecture of the pore, overturning ordered-oligomer models.","evidence":"Cysteine labeling/crosslinking across full-length BAK with mathematical simulation","pmids":["28182867"],"confidence":"High","gaps":["Dynamic in-membrane behavior of clusters not directly visualized"]},{"year":2017,"claim":"Extended VDAC2-BAK regulation to peroxisomes, showing BAK can permeabilize peroxisomal membranes.","evidence":"Organelle-targeted BAK, fractionation, VDAC2/BCL-XL/MCL-1 manipulation","pmids":["28174205"],"confidence":"Medium","gaps":["Single-lab study; physiological role of peroxisomal BAK permeabilization unclear"]},{"year":2018,"claim":"Connected BAK pore formation to innate immunity by showing macropores allow inner-membrane herniation and mtDNA release driving cGAS/STING.","evidence":"Live-cell lattice light-sheet microscopy with caspase inhibition","pmids":["29472455"],"confidence":"High","gaps":["Determinants of macropore versus minimal pore size in vivo not defined"]},{"year":2018,"claim":"Identified Parkin-mediated ubiquitination of the BAK groove as a mitophagy-linked brake on activation, defining a regulatory feedback loop.","evidence":"In vitro ubiquitination, Co-IP, site mutagenesis, BAK activation assays","pmids":["30573668"],"confidence":"High","gaps":["In vivo physiological impact of BAK ubiquitination not quantified"]},{"year":2020,"claim":"Provided structural evidence that membrane lipids bridge BAK dimers, explaining a non-canonical oligomerization interface.","evidence":"Crystal structures of BAK core dimers with lipid/detergent binding sites","pmids":["32929280"],"confidence":"High","gaps":["Lipid bridging in native membranes not directly demonstrated by crystallography"]},{"year":2020,"claim":"Uncovered a neural-specific microexon-NMD mechanism that silences BAK to protect neurons from apoptosis.","evidence":"Splicing analysis, PTBP1 manipulation, NMD assays, germline exon-5 KO mice","pmids":["32710818"],"confidence":"High","gaps":["Whether this regulation operates in human neurons not addressed"]},{"year":2021,"claim":"Defined the BH4 domain and N-terminal region as the conformational switch maintaining inactive BAK.","evidence":"HDX-MS on membrane-bound BAK with mutagenesis and permeabilization assays","pmids":["34523147"],"confidence":"High","gaps":["How BH4 disruption is triggered physiologically not established"]},{"year":2022,"claim":"Distinguished BAK and BAX kinetics, showing BAK seeds and accelerates BAX assembly into shared pores controlling mtDNA release rate.","evidence":"Single-molecule and super-resolution imaging with cGAS/STING assays","pmids":["35120587"],"confidence":"High","gaps":["Molecular basis of BAK's faster kinetics not fully resolved"]},{"year":2024,"claim":"Showed unsaturated lipids proximal to BAK and the desaturase FADS2 promote pore activity and downstream innate immune signaling.","evidence":"Nanodisc lipidomics, membrane pore assays, MD simulations, FADS2 manipulation","pmids":["38830851"],"confidence":"High","gaps":["How lipid composition is locally remodeled at the pore not defined"]},{"year":2024,"claim":"Established the sequence of endogenous pore assembly, with BAK recruited before BAX into unordered mosaic rings.","evidence":"STED super-resolution imaging in WT, BAX-KO, and BAK-KO cells","pmids":["38503846"],"confidence":"High","gaps":["Functional significance of BAK-first recruitment for pore output not quantified"]},{"year":2002,"claim":"Identified plant BAK1 (a distinct LRR receptor kinase) as a BRI1 interactor that activates kinase signaling by transphosphorylation in brassinosteroid signaling.","evidence":"Yeast two-hybrid, in planta Co-IP, overexpression/knockout phenotypes","pmids":["12150928"],"confidence":"High","gaps":["Note: unrelated to mammalian BAK; symbol collision within corpus"]},{"year":2007,"claim":"Showed plant BAK1 is a coreceptor for immune receptors, forming ligand-dependent FLS2 complexes during pattern-triggered immunity.","evidence":"Ligand-dependent in planta Co-IP, bak1 mutant flagellin response assays (replicated by independent lab)","pmids":["17625569","17626179"],"confidence":"High","gaps":["Distinct protein from mammalian BAK; included only for corpus coherence"]},{"year":2024,"claim":"Resolved structural and allosteric mechanisms of plant BAK1 coreceptor activation by partner receptors.","evidence":"Crystal structure of MIK2-SCOOP-BAK1 ternary complex; HDX-MS of EFR-BAK1 allostery","pmids":["39511418","39028038"],"confidence":"High","gaps":["Plant BAK1 biology is orthogonal to mammalian BAK in this timeline"]},{"year":null,"claim":"The corpus conflates two unrelated proteins under one symbol; how endogenous death signals coordinate VDAC2/BCL-XL release, lipid remodeling, and macropore sizing in vivo to tune cGAS/STING output remains unresolved for mammalian BAK.","evidence":"No single discovery integrates upstream restraint release with quantitative pore output in vivo","pmids":[],"confidence":"High","gaps":["Quantitative coupling of restraint displacement to pore size unknown","Tissue-specific weighting of regulatory layers undefined","Symbol collision precludes a unified single-gene mechanism"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[11,18]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[10,19]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[24,32]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[23,24,31,33]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,6,8]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3]},{"term_id":"GO:0005777","term_label":"peroxisome","supporting_discovery_ids":[16]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[22,28,41]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,5,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,9,22]}],"complexes":["FLS2-BAK1 receptor complex (plant)","RLP23-SOBIR1-BAK1 complex (plant)","MIK2-SCOOP-BAK1 complex (plant)"],"partners":["VDAC2","BCL-XL","MCL1","MFN1","MFN2","BAX","BRI1","FLS2"],"other_free_text":["Timeline conflates mammalian proapoptotic BAK and plant LRR coreceptor kinase BAK1/SERK3 under one symbol (collision)."]}},"prefetch_data":{"uniprot":{"accession":"Q16611","full_name":"Bcl-2 homologous antagonist/killer","aliases":["Apoptosis regulator BAK","Bcl-2-like protein 7","Bcl2-L-7"],"length_aa":211,"mass_kda":23.4,"function":"Plays a role in the mitochondrial apoptotic process. Upon arrival of cell death signals, promotes mitochondrial outer membrane (MOM) permeabilization by oligomerizing to form pores within the MOM. This releases apoptogenic factors into the cytosol, including cytochrome c, promoting the activation of caspase 9 which in turn processes and activates the effector caspases","subcellular_location":"Mitochondrion outer membrane","url":"https://www.uniprot.org/uniprotkb/Q16611/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BAK1","classification":"Not Classified","n_dependent_lines":262,"n_total_lines":1208,"dependency_fraction":0.21688741721854304},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/BAK1","total_profiled":1310},"omim":[{"mim_id":"620751","title":"RETROTRANSPOSON GAG-LIKE 10; RTL10","url":"https://www.omim.org/entry/620751"},{"mim_id":"620138","title":"MYOPATHY WITH MYALGIA, INCREASED SERUM CREATINE KINASE, AND WITH OR WITHOUT EPISODIC RHABDOMYOLYSIS 1; MMCKR1","url":"https://www.omim.org/entry/620138"},{"mim_id":"618623","title":"HIG1 HYPOXIA-INDUCIBLE DOMAIN FAMILY, MEMBER 1A; HIGD1A","url":"https://www.omim.org/entry/618623"},{"mim_id":"617081","title":"OMA1 ZINC METALLOPEPTIDASE; OMA1","url":"https://www.omim.org/entry/617081"},{"mim_id":"616695","title":"SERINE/THREONINE/TYROSINE-INTERACTING PROTEIN-LIKE 1; STYXL1","url":"https://www.omim.org/entry/616695"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/BAK1"},"hgnc":{"alias_symbol":["BCL2L7","BAK"],"prev_symbol":["CDN1"]},"alphafold":{"accession":"Q16611","domains":[{"cath_id":"1.10.437.10","chopping":"21-208","consensus_level":"high","plddt":83.3384,"start":21,"end":208}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16611","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q16611-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q16611-F1-predicted_aligned_error_v6.png","plddt_mean":81.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BAK1","jax_strain_url":"https://www.jax.org/strain/search?query=BAK1"},"sequence":{"accession":"Q16611","fasta_url":"https://rest.uniprot.org/uniprotkb/Q16611.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q16611/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16611"}},"corpus_meta":[{"pmid":"11326099","id":"PMC_11326099","title":"Proapoptotic BAX and BAK: 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agents).\",\n      \"method\": \"Genetic double-knockout (Bax-/- Bak-/- mouse embryonic fibroblasts), cytochrome c release assay, apoptosis assays with multiple stimuli\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with multiple orthogonal stimuli and cytochrome c release assay; replicated across multiple death signals in a landmark study\",\n      \"pmids\": [\"11326099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In viable cells, BAK is maintained in an inactive monomeric conformation at the mitochondrial outer membrane by direct interaction with VDAC2 (but not VDAC1). VDAC2 specifically binds the inactive conformer of BAK; death signals (e.g., tBID, BIM, BAD) displace VDAC2 from BAK, enabling BAK homo-oligomerization and apoptosis. VDAC2 deficiency enhances BAK oligomerization and apoptosis susceptibility; VDAC2 overexpression prevents BAK activation.\",\n      \"method\": \"Co-immunoprecipitation, VDAC2-knockout and overexpression cells, BAK oligomerization assays, apoptosis assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic KO, and overexpression with multiple orthogonal readouts in a single rigorous study\",\n      \"pmids\": [\"12881569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Mitochondria-localized p53 directly interacts with BAK, causing BAK oligomerization and cytochrome c release. Formation of the p53-BAK complex coincides with loss of the BAK-MCL1 interaction, suggesting p53 displaces MCL1 to activate BAK.\",\n      \"method\": \"Co-immunoprecipitation, cytochrome c release assay, mitochondrial fractionation\",\n      \"journal\": \"Nature Cell Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and functional cytochrome c release assay in a single lab study\",\n      \"pmids\": [\"15077116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"BAK (and BAX) can localize to the endoplasmic reticulum in addition to mitochondria. ER-targeted BAK causes progressive ER Ca2+ depletion and caspase-12 cleavage, demonstrating a distinct ER-based apoptotic pathway separable from the mitochondrial pathway.\",\n      \"method\": \"Subcellular targeting constructs, fractionation, Ca2+ measurements, caspase cleavage assays in Bax-/-Bak-/- cells reconstituted with compartment-targeted mutants\",\n      \"journal\": \"Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic background (DKO cells), organelle-targeted mutants, multiple orthogonal readouts (Ca2+, caspase cleavage, cytochrome c)\",\n      \"pmids\": [\"12847083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"BAK uniquely interacts with mitofusins MFN1 and MFN2 at the mitochondrial outer membrane. During apoptosis, BAK dissociates from MFN2 and enhances association with MFN1; BH3-domain mutation prevents MFN2 dissociation and diminishes BAK's mitochondrial fragmentation activity. BAK (but not BAX) drives mitochondrial fragmentation during apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, Bak-deficient MEFs and primary neurons, reconstitution in DKO cells, BH3 domain mutagenesis, mitochondrial morphology imaging\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, genetic KO in multiple cell types, mutagenesis, and reconstitution with multiple orthogonal readouts\",\n      \"pmids\": [\"17606912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BID BH3 helix activates BAK by engaging the canonical BH3-binding groove (activation site) of BAK via a 'hit-and-run' mechanism: BID binds transiently, then dissociates, allowing BAK oligomerization at the same overlapping interface. BAK BH1 groove mutation prevents MOMP but not BID binding; BAK BH3 mutations allow BID binding and activation but block oligomerization. BH3-only proteins NOXA and BAD do not activate BAK.\",\n      \"method\": \"NMR solution structure of BID BH3-BAK complex, site-directed mutagenesis, liposomal cytochrome c release assay, MOMP assay\",\n      \"journal\": \"Nature Structural & Molecular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure combined with mutagenesis and functional in vitro reconstitution in a single rigorous study\",\n      \"pmids\": [\"23604079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Full-length BAK resides constitutively at the outer mitochondrial membrane and requires direct BH3 ligand interaction at its canonical BH3-binding groove (not the α1/α6 site used by BAX) to be activated and release cytochrome c. Photoreactive BH3 crosslinking mapped the BAK trigger site to the BH3-binding pocket, distinct from the BAX α1/α6 trigger site.\",\n      \"method\": \"In vitro reconstitution with purified full-length BAK, liposomal release assay, photoreactive BH3 crosslinking, mutagenesis-based solubilization\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution, photocrosslinking, and mutagenesis in a single study establishing distinct BAK vs BAX activation sites\",\n      \"pmids\": [\"23404709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BAK undergoes conformational separation of core and latch domains upon activation by specific BH3 peptides, analogous to BAX. Crystal structure of the BAK core domain dimer reveals the symmetric homodimer as a key intermediate in pore-forming oligomer assembly.\",\n      \"method\": \"Crystal structure of BAK core domain dimer, crosslinking experiments, BH3 peptide activation assays\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with crosslinking and functional activation assays\",\n      \"pmids\": [\"25175025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"After BAK/BAX activation and cytochrome c release during apoptosis, large BAK/BAX macropores appear in the mitochondrial outer membrane, allowing the inner mitochondrial membrane to herniate into the cytosol and carry mitochondrial matrix contents including mtDNA, thereby enabling cGAS/STING activation.\",\n      \"method\": \"Live-cell lattice light-sheet microscopy in mouse embryonic fibroblasts, caspase inhibition experiments\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct live-cell visualization with lattice light-sheet microscopy, mechanistic link to innate immune signaling established\",\n      \"pmids\": [\"29472455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"BAK and BAX present distinct oligomerization properties: BAK organizes into smaller structures with faster kinetics than BAX. BAK recruits and accelerates BAX assembly into oligomers, and both co-assemble into the same apoptotic pores. The relative availability of BAX and BAK determines apoptotic pore growth rate and kinetics of mtDNA release, with consequences for cGAS/STING activation.\",\n      \"method\": \"Single-molecule imaging, super-resolution microscopy, kinetic analysis of oligomerization, pore visualization, cGAS/STING pathway assays\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biophysical and cell biological methods establishing distinct kinetics and cooperative assembly\",\n      \"pmids\": [\"35120587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Disordered clusters of BAK dimers (not ordered oligomers) generate lipidic pores in the mitochondrial outer membrane. Cysteine labeling and linkage analysis across full-length BAK showed the N-terminus is mobile and solvent-exposed post-activation, while dimer-dimer interactions are more labile than BH3:groove interactions within dimers. Mathematical simulations support a disordered dimer-cluster pore model.\",\n      \"method\": \"Cysteine labeling, disulfide crosslinking, mathematical simulations of dimer arrangement\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — comprehensive cysteine-scanning crosslinking across full-length BAK combined with quantitative modeling\",\n      \"pmids\": [\"28182867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal structures of human BAK core domain dimers reveal preferred binding sites for membrane lipids and detergents on the dimer surface. Phospholipid headgroup and one acyl chain (sn2) associate with one core dimer while the other acyl chain (sn1) associates with a neighboring dimer, suggesting lipids bridge BAK dimers to promote oligomerization, unlike typical protein-protein interfaces.\",\n      \"method\": \"Crystal structures of BAK core domain dimers, lipid-binding analysis\",\n      \"journal\": \"Nature Structural & Molecular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with lipid-binding sites identified, providing structural mechanism for lipid-mediated oligomerization\",\n      \"pmids\": [\"32929280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Hydrogen-deuterium exchange mass spectrometry of membrane-bound BAK revealed that the BH4 domain maintains the inactive conformation of BAK; disrupting the BH4 domain is sufficient for constitutive BAK activation. The entire N-terminal region preceding BAK oligomerization domains becomes disordered post-activation and remains disordered in the activated oligomer. Removal of the disordered N-terminus slightly potentiates BAK-mediated membrane permeabilization.\",\n      \"method\": \"HDX-MS on membrane-bound BAK (liposomes with mitochondrial lipids), site-directed mutagenesis, liposomal and mitochondrial permeabilization assays\",\n      \"journal\": \"EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — HDX-MS structural analysis combined with mutagenesis and functional reconstitution, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"34523147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"During mitophagy, Parkin directly ubiquitinates BAK at a conserved lysine in its hydrophobic groove (critical for BH3-only protein activation and homo-dimerization), inhibiting BAK activation and lethal oligomer formation. BAK-dependent MOMP during apoptosis also promotes PINK1-dependent Parkin activation, creating a feedback loop.\",\n      \"method\": \"In vitro ubiquitination assay, Co-IP, BAK activation assay, mitophagy induction, mutagenesis of ubiquitination site\",\n      \"journal\": \"EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro ubiquitination reconstitution, site-specific mutagenesis, and functional BAK activity assays with multiple orthogonal methods\",\n      \"pmids\": [\"30573668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Vitamin K2 (menaquinone) covalently binds to BAK at cysteine-166, inducing BAK oligomerization and BAK-dependent cytochrome c release and apoptosis. This effect is specific to BAK and does not require BAX; VK2-2,3-epoxide (intracellular metabolite) mediates the covalent attachment.\",\n      \"method\": \"Pulldown/binding assay, site-directed mutagenesis (C166), cytochrome c release assay, BAK-specific siRNA knockdown\",\n      \"journal\": \"Molecular Pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding with mutagenesis identifying covalent modification site, functional validation with siRNA, single lab\",\n      \"pmids\": [\"23229512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Neural-specific splicing of the evolutionarily conserved Bak1 microexon 5 (regulated by PTBP1 downregulation during neuronal development) triggers nonsense-mediated mRNA decay of Bak1 transcripts, suppressing pro-apoptotic BAK1 protein expression in neurons. Germline heterozygous ablation of exon 5 increases BAK1 protein exclusively in the brain, increases neuronal apoptosis, and causes early postnatal mortality.\",\n      \"method\": \"Alternative splicing analysis, PTBP1 knockdown/knockout, NMD assays, germline exon 5 knockout mice, neuronal apoptosis quantification\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic model with multiple orthogonal methods (splicing, NMD, KO mice, apoptosis quantification) establishing a neural-specific regulatory mechanism\",\n      \"pmids\": [\"32710818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The VDAC2-BAK axis regulates peroxisomal membrane permeability. Loss of VDAC2 shifts BAK localization from mitochondria to peroxisomes, causing peroxisomal deficiency. Peroxisome-targeted BAK causes release of peroxisomal matrix proteins to the cytosol; BAK activators PUMA and BIM permeabilize peroxisomes in a BAK-dependent manner.\",\n      \"method\": \"Subcellular fractionation, peroxisome-targeted BAK constructs, BAK knockdown, overexpression of VDAC2/BCL-XL/MCL-1\",\n      \"journal\": \"Journal of Cell Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — organelle-targeted constructs and genetic KD with functional peroxisomal permeability readout, single lab\",\n      \"pmids\": [\"28174205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Bcl-xL physiologically restrains BAK by direct physical interaction via BAK's BH3:groove interface. A BAK Q75L (mouse)/Q77L (human) mutation specifically disrupts BAK-BCL-XL binding without affecting BAK structure or killing activity, reducing affinity through loss of a single hydrogen bond. In vivo, loss of BCL-XL binding to BAK causes significant defects in T-cell and platelet survival.\",\n      \"method\": \"Site-directed mutagenesis, binding affinity measurements, knockin mouse model, T-cell and platelet survival analysis\",\n      \"journal\": \"Genes & Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — precision mutagenesis with in vitro affinity measurement and in vivo knockin mouse validation\",\n      \"pmids\": [\"27198225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Unsaturated lipids enriched in the proximal membrane environment of BAK promote BAX pore activity. Lipidomics of BAK isolated in lipid nanodiscs shows enrichment of unsaturated species near BAK during apoptosis. The fatty acid desaturase FADS2 enhances apoptosis sensitivity and cGAS/STING activation downstream of mtDNA release.\",\n      \"method\": \"Comparative lipidomics (lipid nanodisc isolation of BAK), model membrane pore assays, isolated mitochondria assays, molecular dynamics simulations, FADS2 manipulation\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — lipidomics, in vitro reconstitution, MD simulations, and cellular validation in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"38830851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BAK and BAX form stable protein-permeable pores of tunable, dynamic size in lipid membranes. Single-vesicle imaging showed cBid-activated BAK (BakΔC21) forms pores large enough to release not only cytochrome c but also 104 kDa allophycocyanin. Pore area evolves with time and protein concentration but not cardiolipin concentration, consistent with proteolipidic pore nature.\",\n      \"method\": \"Single-vesicle fluorescence assay, size-exclusion analysis, protein concentration titration, cardiolipin manipulation\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution at single-vesicle level with systematic mechanistic dissection\",\n      \"pmids\": [\"24100034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Myc-induced AMPK activation stabilizes p53 via Ser15 phosphorylation, leading to mitochondrial p53 accumulation. Mitochondrial p53 interacts with the BAK-BCL-XL complex, inducing BAK conformational activation without disrupting the BAK-BCL-XL interaction. Subsequent release of activated BAK from this complex leads to spontaneous BAK oligomerization and apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, BAK conformational activation assay, AMPK inhibition, p53 knockdown, mitochondrial fractionation\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and conformational activation assays, single lab, multiple pathway manipulations\",\n      \"pmids\": [\"23589839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Endogenous BAK is recruited to apoptotic pores before BAX. Both BAK and BAX together form unordered mosaic rings on the mitochondrial outer membrane in wild-type cells. In single-knockout cells, either protein alone can form rings independently. Overexpression of BAK produces novel structures absent in non-overexpressing apoptotic cells.\",\n      \"method\": \"Live- and fixed-cell STED super-resolution microscopy in wild-type, BAX-KO, and BAK-KO cells and human primary cells\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct super-resolution imaging in endogenous-expression conditions and multiple genetic backgrounds\",\n      \"pmids\": [\"38503846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In Arabidopsis, BAK1 (SERK3) forms a ligand-dependent complex with the immune receptor FLS2 within minutes of flagellin stimulation. BAK1 positively regulates early and late flagellin-triggered immune responses (including FLS2 and EFR signaling) independently of its role in brassinosteroid signaling.\",\n      \"method\": \"Co-immunoprecipitation in planta (ligand-dependent), bak1 mutant analysis, flagellin response assays, brassinosteroid sensitivity controls\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo Co-IP with ligand-dependence established, genetic mutant analysis, and multiple response readouts; replicated by independent lab in PMID:17626179\",\n      \"pmids\": [\"17625569\", \"17626179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Arabidopsis BAK1 was identified as a specific interactor of BRI1 (brassinosteroid receptor) by yeast two-hybrid. BAK1/BRI1 interaction activates their kinase activities through transphosphorylation in yeast. BAK1 and BRI1 share subcellular localization and physically associate in plants. BAK1 overexpression phenocopies BRI1 overexpression; bak1 knockout gives a weak bri1-like phenotype.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in plants, overexpression/knockout genetic analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid plus in planta Co-IP plus reciprocal genetic overexpression and knockout phenotypes; landmark study\",\n      \"pmids\": [\"12150928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"BRI1 transphosphorylates BAK1 in vitro on specific kinase-domain residues critical for BAK1 function; BR-dependent BRI1 activation precedes BAK1 association in planta. BAK1 subsequently transphosphorylates BRI1, quantitatively increasing BRI1 kinase activity. A sequential transphosphorylation model is proposed: BRI1 controls signaling specificity, then activates BAK1 via transphosphorylation, and BAK1 reciprocally enhances BRI1.\",\n      \"method\": \"In vitro kinase assay with phosphosite mapping (mass spectrometry), in planta phosphorylation analysis, temporal dissection of BR signaling\",\n      \"journal\": \"Developmental Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase reconstitution with phosphosite identification by MS and in planta validation\",\n      \"pmids\": [\"18694562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BIR2, a novel BAK1-interacting receptor-like kinase (identified by LC/ESI-MS/MS), is unidirectionally phosphorylated by BAK1. BIR2 constitutively interacts with BAK1, preventing BAK1-FLS2 complex formation in the absence of ligand. PAMP perception triggers BIR2 release from BAK1, enabling BAK1 recruitment to the FLS2 complex. BIR2 acts as a negative regulator of PAMP-triggered immunity.\",\n      \"method\": \"LC/ESI-MS/MS interactome, Co-immunoprecipitation, bir2 mutant phenotyping, phosphorylation assays\",\n      \"journal\": \"Current Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS-based interactome identification, reciprocal Co-IP, genetic mutant, and phosphorylation assays with multiple orthogonal methods\",\n      \"pmids\": [\"24388849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Protein phosphatase 2A (PP2A), composed of subunits A1, C4, and B'η/ζ, constitutively associates with BAK1 in planta and dephosphorylates BAK1 to negatively regulate plant innate immunity. Impairment of PP2A-BAK1 interaction increases steady-state BAK1 phosphorylation and potentiates immune responses.\",\n      \"method\": \"Co-immunoprecipitation, PP2A mutant analysis, phosphorylation assays, immune response measurements\",\n      \"journal\": \"EMBO Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and phosphorylation analysis with genetic validation, single lab study\",\n      \"pmids\": [\"25085430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BAK1 directly interacts with and phosphorylates CNGC20 (a Ca2+-permeable channel) at specific sites in its C-terminal cytosolic domain, regulating CNGC20 protein stability and Ca2+ channel function. This BAK1-CNGC20 axis controls cellular Ca2+ homeostasis to contain cell death in Arabidopsis.\",\n      \"method\": \"RNAi genetic screen, Co-IP, in vitro kinase/phosphorylation assay, electrophysiology, genetic epistasis\",\n      \"journal\": \"Current Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro phosphorylation assay and Co-IP with genetic validation, single lab\",\n      \"pmids\": [\"31679931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BAK1 undergoes Ca2+-dependent proteolytic cleavage at a surface-exposed Asp287 residue, conserved in Arabidopsis, N. benthamiana, and yeast. This cleavage is regulated by developmental cues and immune stimulation. The BAK1 D287A mutation impairs BAK1 phosphorylation of its substrate BIK1, plasma membrane localization, and BAK1 function in immunity, BR signaling, and cell death containment.\",\n      \"method\": \"Site-directed mutagenesis (D287A), in planta phosphorylation assays, plasma membrane localization imaging, genetic complementation\",\n      \"journal\": \"Plant Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with multiple functional readouts across three organisms, single lab\",\n      \"pmids\": [\"30782965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RLP23 forms a constitutive, ligand-independent complex with SOBIR1, and upon nlp20 (NLP peptide) binding, recruits BAK1 into a tripartite RLP23-SOBIR1-BAK1 complex to activate immune responses.\",\n      \"method\": \"Co-immunoprecipitation in planta, nlp20 binding assay, genetic mutant analysis\",\n      \"journal\": \"Nature Plants\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo Co-IP and ligand-dependent complex formation, single lab\",\n      \"pmids\": [\"27251392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The lectin receptor kinase LecRK-VI.2 constitutively associates with BAK1 in vivo, and both LecRK-VI.2 and BAK1 kinase activities are required for eNAD+/eNADP+ signaling and systemic acquired resistance (SAR) in Arabidopsis.\",\n      \"method\": \"Co-immunoprecipitation in planta, kinase-dead mutant analysis, SAR assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo Co-IP and kinase-dead mutant with functional SAR assay, single lab\",\n      \"pmids\": [\"31641112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BAK1 phosphorylates the plasma membrane H+-ATPase AHA2 at T858 and T881 in its C-terminal domain, enhancing H+ pump activity and promoting K+ uptake under low-potassium stress. BAK1 directly interacts with the AHA2 C-terminus.\",\n      \"method\": \"Co-IP, in vitro kinase assay with phosphosite identification, aha2 and bak1 mutant analysis, phosphorylation-mimic mutants\",\n      \"journal\": \"Plant Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay with phosphosite mapping and genetic validation with phosphomimetic mutants, single lab\",\n      \"pmids\": [\"35604103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EFR can allosterically activate BAK1 kinase activity via a non-catalytic mechanism: a kinase-dead EFR variant retains ability to enhance BAK1 catalytic activity. HDX-MS analysis and suppressor mutagenesis indicate EFR must adopt its active conformation to allosterically activate BAK1 by supporting αC-helix positioning. BAK1 first phosphorylates EFR in the activation loop to stabilize EFR's active conformation, allowing EFR to then allosterically activate BAK1.\",\n      \"method\": \"HDX-MS, kinase-dead mutant analysis, homology-based intragenic suppressor mutagenesis, in vitro kinase assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — HDX-MS structural analysis, mutagenesis, and in vitro kinase reconstitution establishing non-catalytic allosteric activation mechanism\",\n      \"pmids\": [\"39028038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BAK1 is phosphorylated by and interacts with all three Arabidopsis catalases (CAT1, CAT2, CAT3), identified by affinity purification/LC-MS/MS. BAK1-mediated catalase phosphorylation enhances catalase activity and reduces H2O2 accumulation under high light, regulating plant growth. BAK1 overexpression effect on high-light growth is abolished in triple catalase knockout plants.\",\n      \"method\": \"Affinity purification/LC-MS/MS, in vitro kinase assay with phosphosite mapping, genetic analysis (bak1 and cat mutants)\",\n      \"journal\": \"International Journal of Molecular Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction, in vitro phosphorylation, and genetic validation, single lab\",\n      \"pmids\": [\"32093294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The receptor-like kinase NIK1 negatively regulates FLS2/BAK1 complex formation. NIK1 interacts with both FLS2 and BAK1; this interaction is enhanced upon flg22 perception. NIK1 acts as a negative regulator of antibacterial PTI while positively regulating antiviral immunity.\",\n      \"method\": \"Co-immunoprecipitation, NIK1 overexpression/knockout, PTI response assays, bacterial resistance assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo Co-IP with ligand-dependent enhancement and genetic analysis, single lab\",\n      \"pmids\": [\"31676803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cell death in bak1 bkk1 double mutants is suppressed by mutation of the NLR helper proteins ADR1s, indicating BAK1 depletion triggers NLR-dependent ETI-like cell death. Pseudomonas effector HopB1, which proteolytically cleaves activated BAK1, triggers cell death in an ADR1-dependent manner, suggesting BAK1 and its paralogs are guarded by NLRs.\",\n      \"method\": \"Genetic epistasis (bak1 bkk1 adr1 triple mutants), HopB1 expression/delivery, protease activity analysis\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with NLR mutants and bacterial effector delivery, single lab\",\n      \"pmids\": [\"33055218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BAK1 and BKK1-mediated cell death control requires nucleocytoplasmic trafficking; loss-of-function of nucleoporin NUP85-like gene SBB1 (and other nucleoporins in the same sub-complex) or DEAD-box RNA helicase DRH1 suppresses bak1 bkk1 cell death. Suppression correlates with blocked poly(A)+ RNA export and reduced salicylic acid accumulation.\",\n      \"method\": \"Genetic suppressor screen, epistasis analysis, mRNA export assays, salicylic acid measurements\",\n      \"journal\": \"Plant Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis from suppressor screen with mRNA export and SA mechanistic readouts, single lab\",\n      \"pmids\": [\"26775605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Kinase activity of both SOBIR1 and BAK1 is required for SOBIR1-induced constitutive immunity and SOBIR1 phosphorylation in planta. BAK1 kinase activity is essential for the defense response triggered by the tomato LRR-RLP Cf-4. SOBIR1 and BAK1 likely transphosphorylate each other within the signaling-competent receptor complex.\",\n      \"method\": \"Kinase-dead mutant analysis, phosphorylation assays, gene silencing, co-immunoprecipitation, live cell imaging\",\n      \"journal\": \"Molecular Plant Pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase-dead mutants with phosphorylation and functional assays, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"30407725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Crystal structure of MIK2-SCOOP-BAK1 complex reveals that SCOOPs use their SxS motif to bind MIK2 and carboxy-terminal GGR residues to bridge MIK2 to BAK1. Specific N-glycans on MIK2 directly interact with BAK1 upon SCOOP sensing; loss of this N-glycosylation site does not affect MIK2 localization or conformation but markedly reduces MIK2-BAK1 affinity and abolishes SCOOP-triggered immunity.\",\n      \"method\": \"Crystal structure of ternary complex, N-glycosylation mutagenesis, binding affinity measurements, genetic complementation\",\n      \"journal\": \"Nature Plants\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis, binding measurements, and in planta functional validation\",\n      \"pmids\": [\"39511418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BAK1-dependent PTI contributes to antiviral resistance in Arabidopsis; bak1 mutants show increased susceptibility to three RNA viruses. Crude viral extracts (but not purified virions) induce PTI marker responses in a BAK1-dependent manner.\",\n      \"method\": \"bak1 mutant viral infection assays, PTI marker response assays with viral extracts vs purified virions\",\n      \"journal\": \"Molecular Plant-Microbe Interactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mutant analysis with multiple viruses and functional PTI readouts, single lab\",\n      \"pmids\": [\"23902263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BAK1 is involved in AtRALF1-induced inhibition of root cell expansion. AtRALF1 physically interacts with BAK1 (Kd = 4.6 μM), induces BAK1 phosphorylation, and requires BAK1 for induction of AtRALF1-responsive genes. Binding to intact seedlings is partly BAK1-dependent.\",\n      \"method\": \"Binding affinity measurement (acridinium-labeled peptide), Co-IP, bak1 mutant analysis, phosphorylation assay, gene expression analysis\",\n      \"journal\": \"PLoS Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay with Kd measurement, phosphorylation evidence, and genetic validation, single lab\",\n      \"pmids\": [\"29028796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Visualization by FLIM in live Arabidopsis root epidermal cells showed BR signaling activation increases BAK1-BRI1 heterooligomerization by ~50% at the plasma membrane. Approximately 7% of the BRI1 PM pool constitutively heterooligomerizes with BAK1 independent of BR ligand.\",\n      \"method\": \"Comparative colocalization analysis and FLIM (fluorescence lifetime imaging microscopy) in live plant cells\",\n      \"journal\": \"Plant Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct live-cell FLIM imaging quantifying receptor heterooligomerization, single lab\",\n      \"pmids\": [\"23796795\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BAK1 (human/mammalian BAK) is a proapoptotic BCL-2 family multidomain protein constitutively localized to the mitochondrial outer membrane (restrained in inactive monomer form by VDAC2 and BCL-XL), which upon activation by direct BH3-only protein binding at its canonical BH3-binding groove undergoes conformational separation of core and latch domains, forms symmetric homodimers that assemble into disordered clusters bridged partly by membrane lipids (especially unsaturated species), and generates proteolipidic macropores that release cytochrome c, Smac/DIABLO, and ultimately mitochondrial DNA to activate cGAS/STING-dependent innate immunity; BAK activation is negatively regulated by VDAC2 binding, BCL-XL restraint, Parkin-mediated ubiquitination of its hydrophobic groove, and neural-specific NMD of its mRNA via PTBP1-regulated microexon splicing; BAK also permeabilizes ER and peroxisomal membranes and regulates mitochondrial morphology by interacting with mitofusins, while the plant ortholog/namesake BAK1 (BRI1-ASSOCIATED RECEPTOR KINASE 1) is an LRR-receptor-like kinase coreceptor that transphosphorylates ligand-binding receptor kinases (BRI1, FLS2, EFR, MIK2) and is itself regulated by PP2A dephosphorylation, BIR2-mediated sequestration, proteolytic cleavage at D287, and allosteric activation by its partner receptors.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"The symbol BAK1 in this timeline maps to two entirely distinct, unrelated proteins that share only a name: mammalian BAK, a proapoptotic BCL-2 family pore-forming protein, and Arabidopsis BAK1 (SERK3), a plant leucine-rich-repeat receptor-like kinase coreceptor. Because both are internally coherent and supported by High-confidence evidence, each is summarized in turn. Mammalian BAK is an essential effector of mitochondrial outer membrane permeabilization (MOMP) during apoptosis: together with BAX it forms the indispensable gateway whose loss renders cells resistant to diverse death stimuli [#0]. In viable cells BAK is held in an inactive monomeric conformation at the mitochondrial outer membrane through direct binding by VDAC2 and BCL-XL, with the BH4 domain stabilizing the latent state [#1, #12, #17]. Activation requires transient \\\"hit-and-run\\\" engagement of the canonical BH3-binding groove by BH3-only ligands such as BID, a trigger site distinct from the BAX \\u03b11/\\u03b16 site [#5, #6]; this drives separation of the core and latch domains and assembly of symmetric core-domain homodimers [#7]. Dimers coalesce into disordered clusters bridged in part by membrane lipids\\u2014particularly unsaturated species\\u2014to generate dynamically sized proteolipidic macropores that release cytochrome c and larger matrix contents [#10, #11, #18, #19]. These macropores permit inner-membrane herniation and mtDNA release that activates cGAS/STING innate immunity, with BAK recruited ahead of BAX and accelerating its co-assembly into shared apoptotic pores [#8, #9, #21]. BAK also permeabilizes ER and peroxisomal membranes and remodels mitochondrial morphology via mitofusin interactions [#3, #16, #4], and is negatively regulated by Parkin-mediated ubiquitination of its groove and by neural-specific NMD of its transcript [#13, #15]. In contrast, plant BAK1 is a coreceptor LRR-kinase that transphosphorylates and is reciprocally activated by ligand-binding receptor kinases including BRI1 in brassinosteroid signaling and FLS2/EFR/MIK2 in pattern-triggered immunity [#23, #24, #22, #38, #32]. This dual occupancy of one symbol reflects nomenclatural collision rather than a single biological entity.\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that BAK, redundantly with BAX, is the obligatory effector gateway for mitochondrial apoptosis, defining the genetic requirement for cytochrome c release.\",\n      \"evidence\": \"Bax-/- Bak-/- MEFs challenged with multiple death stimuli and cytochrome c release assays\",\n      \"pmids\": [\"11326099\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the molecular conformational steps of BAK activation\", \"Relative contributions of BAK vs BAX not separated\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified VDAC2 as the direct restraint that keeps inactive BAK monomeric, explaining how BAK is held in check in viable cells.\",\n      \"evidence\": \"Reciprocal Co-IP, VDAC2 KO and overexpression, BAK oligomerization and apoptosis readouts\",\n      \"pmids\": [\"12881569\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of VDAC2 selectivity for inactive BAK not defined\", \"How death signals displace VDAC2 mechanistically not resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed BAK function extends beyond mitochondria to the ER, defining a Ca2+-dependent ER apoptotic pathway.\",\n      \"evidence\": \"Compartment-targeted BAK constructs in DKO cells with Ca2+ and caspase-12 readouts\",\n      \"pmids\": [\"12847083\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous contribution of ER-localized BAK versus mitochondrial pool unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Linked the p53 tumor suppressor directly to BAK activation, providing a transcription-independent route to MOMP.\",\n      \"evidence\": \"Co-IP and cytochrome c release with mitochondrial fractionation\",\n      \"pmids\": [\"15077116\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab Co-IP; whether p53 directly activates or displaces MCL1 not disentangled\", \"Stoichiometry and affinity of p53-BAK not measured\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Distinguished BAK from BAX by its mitofusin interactions controlling mitochondrial fragmentation during apoptosis.\",\n      \"evidence\": \"Co-IP, Bak-deficient MEFs/neurons, BH3 mutagenesis, morphology imaging\",\n      \"pmids\": [\"17606912\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic coupling of MFN switching to pore formation not established\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved the activation trigger site, showing BH3-only ligands engage BAK's canonical groove via a transient hit-and-run mechanism distinct from the BAX trigger site.\",\n      \"evidence\": \"NMR of BID BH3-BAK, photoreactive crosslinking, mutagenesis, liposomal release assays\",\n      \"pmids\": [\"23604079\", \"23404709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How transient ligand binding is converted to stable oligomer not fully detailed\", \"Which endogenous BH3-only proteins dominate in different cell types unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Characterized BAK pores as protein-permeable structures of tunable size, defining their proteolipidic nature.\",\n      \"evidence\": \"Single-vesicle fluorescence with size-exclusion and concentration/cardiolipin titration\",\n      \"pmids\": [\"24100034\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Native pore geometry in intact mitochondria not directly imaged here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the symmetric core-domain homodimer and core/latch separation as the structural intermediate of pore assembly.\",\n      \"evidence\": \"Crystal structure of BAK core dimer with crosslinking and BH3 activation\",\n      \"pmids\": [\"25175025\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How dimers assemble into higher-order pores not resolved by static structure\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated BCL-XL restrains BAK in vivo through the BH3:groove interface, with physiological consequences for lymphocyte and platelet survival.\",\n      \"evidence\": \"Precision Q75L/Q77L mutagenesis, affinity measurement, knockin mice\",\n      \"pmids\": [\"27198225\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative weighting of BCL-XL versus VDAC2 restraint in different tissues not quantified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed the disordered dimer-cluster architecture of the pore, overturning ordered-oligomer models.\",\n      \"evidence\": \"Cysteine labeling/crosslinking across full-length BAK with mathematical simulation\",\n      \"pmids\": [\"28182867\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamic in-membrane behavior of clusters not directly visualized\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended VDAC2-BAK regulation to peroxisomes, showing BAK can permeabilize peroxisomal membranes.\",\n      \"evidence\": \"Organelle-targeted BAK, fractionation, VDAC2/BCL-XL/MCL-1 manipulation\",\n      \"pmids\": [\"28174205\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study; physiological role of peroxisomal BAK permeabilization unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected BAK pore formation to innate immunity by showing macropores allow inner-membrane herniation and mtDNA release driving cGAS/STING.\",\n      \"evidence\": \"Live-cell lattice light-sheet microscopy with caspase inhibition\",\n      \"pmids\": [\"29472455\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of macropore versus minimal pore size in vivo not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified Parkin-mediated ubiquitination of the BAK groove as a mitophagy-linked brake on activation, defining a regulatory feedback loop.\",\n      \"evidence\": \"In vitro ubiquitination, Co-IP, site mutagenesis, BAK activation assays\",\n      \"pmids\": [\"30573668\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo physiological impact of BAK ubiquitination not quantified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided structural evidence that membrane lipids bridge BAK dimers, explaining a non-canonical oligomerization interface.\",\n      \"evidence\": \"Crystal structures of BAK core dimers with lipid/detergent binding sites\",\n      \"pmids\": [\"32929280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lipid bridging in native membranes not directly demonstrated by crystallography\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Uncovered a neural-specific microexon-NMD mechanism that silences BAK to protect neurons from apoptosis.\",\n      \"evidence\": \"Splicing analysis, PTBP1 manipulation, NMD assays, germline exon-5 KO mice\",\n      \"pmids\": [\"32710818\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this regulation operates in human neurons not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the BH4 domain and N-terminal region as the conformational switch maintaining inactive BAK.\",\n      \"evidence\": \"HDX-MS on membrane-bound BAK with mutagenesis and permeabilization assays\",\n      \"pmids\": [\"34523147\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How BH4 disruption is triggered physiologically not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Distinguished BAK and BAX kinetics, showing BAK seeds and accelerates BAX assembly into shared pores controlling mtDNA release rate.\",\n      \"evidence\": \"Single-molecule and super-resolution imaging with cGAS/STING assays\",\n      \"pmids\": [\"35120587\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of BAK's faster kinetics not fully resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed unsaturated lipids proximal to BAK and the desaturase FADS2 promote pore activity and downstream innate immune signaling.\",\n      \"evidence\": \"Nanodisc lipidomics, membrane pore assays, MD simulations, FADS2 manipulation\",\n      \"pmids\": [\"38830851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How lipid composition is locally remodeled at the pore not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established the sequence of endogenous pore assembly, with BAK recruited before BAX into unordered mosaic rings.\",\n      \"evidence\": \"STED super-resolution imaging in WT, BAX-KO, and BAK-KO cells\",\n      \"pmids\": [\"38503846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional significance of BAK-first recruitment for pore output not quantified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified plant BAK1 (a distinct LRR receptor kinase) as a BRI1 interactor that activates kinase signaling by transphosphorylation in brassinosteroid signaling.\",\n      \"evidence\": \"Yeast two-hybrid, in planta Co-IP, overexpression/knockout phenotypes\",\n      \"pmids\": [\"12150928\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Note: unrelated to mammalian BAK; symbol collision within corpus\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed plant BAK1 is a coreceptor for immune receptors, forming ligand-dependent FLS2 complexes during pattern-triggered immunity.\",\n      \"evidence\": \"Ligand-dependent in planta Co-IP, bak1 mutant flagellin response assays (replicated by independent lab)\",\n      \"pmids\": [\"17625569\", \"17626179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Distinct protein from mammalian BAK; included only for corpus coherence\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved structural and allosteric mechanisms of plant BAK1 coreceptor activation by partner receptors.\",\n      \"evidence\": \"Crystal structure of MIK2-SCOOP-BAK1 ternary complex; HDX-MS of EFR-BAK1 allostery\",\n      \"pmids\": [\"39511418\", \"39028038\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Plant BAK1 biology is orthogonal to mammalian BAK in this timeline\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The corpus conflates two unrelated proteins under one symbol; how endogenous death signals coordinate VDAC2/BCL-XL release, lipid remodeling, and macropore sizing in vivo to tune cGAS/STING output remains unresolved for mammalian BAK.\",\n      \"evidence\": \"No single discovery integrates upstream restraint release with quantitative pore output in vivo\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative coupling of restraint displacement to pore size unknown\", \"Tissue-specific weighting of regulatory layers undefined\", \"Symbol collision precludes a unified single-gene mechanism\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [11, 18]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [10, 19]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [24, 32]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [23, 24, 31, 33]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 6, 8]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005777\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [22, 28, 41]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 5, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 9, 22]}\n    ],\n    \"complexes\": [\n      \"FLS2-BAK1 receptor complex (plant)\",\n      \"RLP23-SOBIR1-BAK1 complex (plant)\",\n      \"MIK2-SCOOP-BAK1 complex (plant)\"\n    ],\n    \"partners\": [\n      \"VDAC2\",\n      \"BCL-XL\",\n      \"MCL1\",\n      \"MFN1\",\n      \"MFN2\",\n      \"BAX\",\n      \"BRI1\",\n      \"FLS2\"\n    ],\n    \"other_free_text\": [\n      \"Timeline conflates mammalian proapoptotic BAK and plant LRR coreceptor kinase BAK1/SERK3 under one symbol (collision).\"\n    ]\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}