{"gene":"BEX3","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2000,"finding":"NADE (BEX3) specifically binds to the cell-death domain of p75NTR, and co-expression of NADE with p75NTR induces caspase-2 and caspase-3 activities and nuclear DNA fragmentation in 293T cells. Cell death was NGF-dependent and required both NADE and p75NTR co-expression; NADE alone was insufficient.","method":"Yeast two-hybrid screen, co-expression apoptosis assays in 293T/PC12/nnr5 cells and oligodendrocytes, dose-dependent recruitment assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction confirmed by yeast two-hybrid and functional cell-based assays, replicated across multiple cell lines (293T, PC12, nnr5, oligodendrocytes) in a single rigorous study","pmids":["10764727"],"is_preprint":false},{"year":2002,"finding":"Mutational analysis of NADE (BEX3) defined that residues 41–71 are sufficient to induce apoptosis; the C-terminal regulatory region (residues 72–112) is required for NGF-dependent regulation. Mutations in the leucine-rich nuclear export signal (NES, residues 90–100) abolished nuclear export of NADE, its self-association, interaction with p75NTR, and NGF-dependent apoptosis. A dominant-negative fragment (residues 81–124) blocked NGF-induced apoptosis in oligodendrocytes.","method":"Truncation and point mutagenesis, nuclear export assays, co-immunoprecipitation, apoptosis assays in oligodendrocytes","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis with multiple orthogonal functional readouts (localization, self-association, p75NTR binding, apoptosis) in a single rigorous study","pmids":["11830582"],"is_preprint":false},{"year":2004,"finding":"NADE (BEX3) interacts with Smac/DIABLO; the interaction maps to the N-terminal region of Smac and the C-terminal region of NADE. Co-expression of NADE and Smac promotes TRAIL-induced apoptosis in MCF-7 cells, and their co-presence inhibits XIAP-mediated ubiquitination of Smac.","method":"Yeast two-hybrid/pulldown screen for Smac-binding proteins, co-immunoprecipitation, apoptosis assays, ubiquitination assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction mapped by domain deletion and confirmed by co-IP, functional consequence shown in cell-based assay, single lab","pmids":["15178455"],"is_preprint":false},{"year":2003,"finding":"Human NADE (BEX3) was identified as a binding partner of dynactin by yeast two-hybrid screening; however, p75NTR did not co-immunoprecipitate with human NADE, and cells stably expressing human NADE did not respond to NGF or TNF. Forced NADE expression suppressed tumor growth in vivo (CHO and MDA-MB-231 xenografts) without affecting in vitro growth.","method":"Yeast two-hybrid, co-immunoprecipitation, stable transfection with in vivo xenograft growth assay","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid interaction with dynactin, negative co-IP result for p75NTR, in vivo tumor suppression, single lab","pmids":["12739005"],"is_preprint":false},{"year":2004,"finding":"Bex (BEX3 ortholog) proteins were identified as interaction partners of olfactory marker protein (OMP); the interaction was confirmed by chemical cross-linking of recombinant OMP with a synthetic Bex-derived peptide, and by co-immunoprecipitation. Co-transfection of OMP with Bex results in some OMP appearing in the nucleus, suggesting Bex can alter OMP subcellular localization.","method":"Phage-display screening, chemical cross-linking, co-immunoprecipitation, co-transfection localization in HEK293 cells","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal binding assays (phage display, chemical cross-linking, co-IP) in a single study; functional consequence (nuclear relocalization of OMP) shown but not deeply characterized","pmids":["12911636","15198671"],"is_preprint":false},{"year":2004,"finding":"Bex3 localizes to perinuclear mitochondria undergoing active DNA replication in F9 teratocarcinoma cells, visualized as GFP fusion protein by deconvolution microscopy. Mitochondrial localization requires both the NES and the C-terminal CaaX box. siRNA-mediated reduction of Bex3 levels results in negligible cell growth.","method":"GFP fusion protein deconvolution microscopy, deletion mutagenesis of NES and CaaX motifs, siRNA knockdown with growth assay","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by live imaging with mutagenesis defining required sequences, and loss-of-function growth phenotype; single lab","pmids":["15563833"],"is_preprint":false},{"year":2005,"finding":"Among Bex family members, rat Bex3 (BEX3 ortholog) localizes to the cytoplasm and is degraded by the proteasome, while rat Bex1 and Bex2 are not. Rat Bex3 protein can likely bind transition metals through a histidine-rich domain.","method":"Subcellular fractionation/microscopy of transfected cells, proteasome inhibitor treatment, sequence analysis of histidine-rich domain","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization and proteasome sensitivity shown in transfected cells, single study; metal-binding is predicted from sequence without direct binding assay","pmids":["15958283"],"is_preprint":false},{"year":2007,"finding":"The TSC1 gene product hamartin interacts with NADE (BEX3); the interaction was confirmed by pulldown of endogenous NADE with the immobilized coiled-coil domain of hamartin, and by immunoprecipitation and immunofluorescence in neurons and mouse brain. Hamartin constitutively associates with NADE to prevent its proteasomal degradation; TSC1 siRNA knockdown reduces NADE levels and abolishes NGF-induced apoptosis in PC12h cells.","method":"Yeast two-hybrid, pulldown assay with immobilized coiled-coil domain, co-immunoprecipitation, immunofluorescence, siRNA knockdown with apoptosis readout","journal":"Molecular and cellular neurosciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — interaction confirmed by multiple orthogonal methods (pulldown, co-IP, immunofluorescence) in cells and in vivo tissue, with functional consequence (proteasomal stabilization and apoptosis) established","pmids":["17355907"],"is_preprint":false},{"year":2006,"finding":"DRG-1 (dopamine responsive gene-1) interacts with NADE (BEX3) in vivo and in vitro; the interaction maps to the N-terminal of DRG-1 and the C-terminal of NADE, and occurs in the cytoplasm. Stable expression of DRG-1 promotes cell proliferation, and this is suppressed by NADE overexpression. DRG-1 overexpression increases the S-phase population, implicating NADE in negative regulation of cell cycle progression.","method":"Yeast two-hybrid, co-immunoprecipitation, domain mapping, MTT proliferation assay, flow cytometry cell cycle analysis","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction confirmed by co-IP with domain mapping; functional antagonism shown by orthogonal proliferation and cell cycle assays; single lab","pmids":["16777077"],"is_preprint":false},{"year":2015,"finding":"Bex3 dimerization and nuclear shuttling are required for transcriptional regulation of the trkA promoter. Bex3 associates with a 150 bp region immediately upstream of the trkA transcription start site (confirmed by qChIP). Bex3 enhances basal and NGF-induced trkA promoter activation. shRNA-mediated downregulation of Bex3 increases neuronal apoptosis in NGF-deprived sensory neurons and compromises NGF-induced PC12 differentiation.","method":"qChIP, trkA promoter reporter assays, shRNA knockdown with apoptosis and differentiation readouts in sensory neurons and PC12 cells","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct chromatin association confirmed by qChIP, functional consequence shown by orthogonal reporter assays and loss-of-function in primary neurons and PC12 cells; multiple readouts in a single rigorous study","pmids":["25948268"],"is_preprint":false},{"year":2015,"finding":"Biophysical characterization of recombinant BEX3 by SAXS, AFM, solution NMR, partial proteinase K digestion, circular dichroism, and fluorescence revealed that BEX3 forms a specific higher-order oligomer consistent with a globular molecule, contains ~31% α-helix and ~20% β-strand, has partially folded regions near N- and C-termini, and a proteolysis-resistant core around residues 55–120.","method":"Small angle X-ray scattering (SAXS), atomic force microscopy, solution NMR, circular dichroism, fluorescence spectroscopy, partial proteinase K digestion of recombinant protein","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biophysical methods on recombinant protein providing consistent structural characterization","pmids":["26383250"],"is_preprint":false},{"year":2015,"finding":"Bex proteins (including BEX3) are intrinsically disordered proteins (IDPs), confirmed by circular dichroism spectroscopy of purified Bex1 expressed in E. coli, and bioinformatics analyses showing conserved long disordered regions across all family members.","method":"Bioinformatics disorder prediction, circular dichroism spectroscopy of recombinant Bex1","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — CD spectroscopy performed on Bex1 (not BEX3 directly), bioinformatics extended to BEX3; single study, indirect evidence for BEX3 specifically","pmids":["25612294"],"is_preprint":false},{"year":2017,"finding":"BEX3 knockdown via siRNA in nasopharyngeal carcinoma (NPC) cells significantly reduced OCT4 expression, and shRNA-mediated BEX3 suppression increased NPC cell sensitivity to cisplatin, establishing BEX3 as a regulator of OCT4 expression and cisplatin resistance in NPC.","method":"siRNA knockdown with OCT4 protein quantification, shRNA stable knockdown with cisplatin sensitivity assay","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal loss-of-function approaches with defined molecular (OCT4) and cellular (cisplatin resistance) readouts; single lab","pmids":["28083995"],"is_preprint":false},{"year":2020,"finding":"Two different murine Bex3 alleles result in reduced interneuron number and hippocampal electrophysiological imbalance, with distinct behavioral phenotypes, establishing Bex3 as required for higher brain functions including interneuron development and hippocampal circuit function.","method":"Murine Bex3 allele analysis, histological interneuron quantification, hippocampal electrophysiology, behavioral testing","journal":"Genome biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined morphological, electrophysiological, and behavioral readouts; single study","pmids":["33100228"],"is_preprint":false}],"current_model":"BEX3 (NADE) is an intrinsically disordered, higher-order oligomeric adaptor protein that binds the death domain of p75NTR via a core apoptosis-executing region (residues 41–71), requires a leucine-rich NES (residues 90–100) for nuclear export, self-association, and p75NTR interaction, and mediates NGF-dependent caspase-2/3 activation; it is stabilized against proteasomal degradation by hamartin (TSC1), interacts with Smac/DIABLO to inhibit XIAP-mediated Smac ubiquitination and promote TRAIL-induced apoptosis, interacts with DRG-1 to negatively regulate cell proliferation, shuttles to the nucleus where it binds the trkA promoter to enhance TrkA expression and NGF-dependent neuronal survival/differentiation, localizes to replicating perinuclear mitochondria via its NES and CaaX box, and is required for normal interneuron number and hippocampal circuit function in vivo."},"narrative":{"mechanistic_narrative":"BEX3 (NADE) is an intrinsically disordered, higher-order oligomeric adaptor protein that couples neurotrophin receptor signaling to apoptotic and transcriptional outputs [PMID:10764727, PMID:26383250]. It was first defined as a p75NTR death-domain binding partner whose co-expression drives NGF-dependent caspase-2/3 activation and DNA fragmentation, with an apoptosis-executing core in residues 41–71 and a C-terminal regulatory region (72–112) governing NGF dependence [PMID:10764727, PMID:11830582]. A leucine-rich nuclear export signal (residues 90–100) is required for nuclear export, self-association, and p75NTR binding, and biophysical analysis maps a proteolysis-resistant globular core to residues ~55–120 flanked by partially folded termini [PMID:11830582, PMID:26383250]. BEX3 also acts in the nucleus as a transcriptional regulator: dimerization-dependent shuttling allows it to associate with a region immediately upstream of the trkA transcription start site and enhance basal and NGF-induced TrkA expression, promoting neuronal survival and differentiation [PMID:25948268]. Its abundance is controlled by the proteasome, and the TSC1 product hamartin constitutively binds BEX3 to prevent its degradation, a stabilization required for NGF-induced apoptosis [PMID:17355907]. BEX3 further engages Smac/DIABLO to block XIAP-mediated Smac ubiquitination and promote TRAIL-induced apoptosis, and antagonizes DRG-1-driven proliferation [PMID:15178455, PMID:16777077]. In vivo, two murine Bex3 alleles produce reduced interneuron number and hippocampal circuit imbalance, establishing a requirement for normal brain function [PMID:33100228].","teleology":[{"year":2000,"claim":"Established BEX3/NADE as a death-domain effector that links p75NTR to the apoptotic machinery, answering how the receptor triggers cell death.","evidence":"Yeast two-hybrid against p75NTR plus co-expression apoptosis assays in 293T, PC12, nnr5 and oligodendrocytes","pmids":["10764727"],"confidence":"High","gaps":["Did not define the structural basis or the BEX3 residues mediating the interaction","Downstream of caspase activation left unresolved"]},{"year":2002,"claim":"Mapped the functional architecture of BEX3, showing distinct apoptosis-executing and regulatory regions and that a leucine-rich NES couples export, self-association, and p75NTR binding to apoptosis.","evidence":"Truncation/point mutagenesis with nuclear export, co-IP, and apoptosis readouts in oligodendrocytes","pmids":["11830582"],"confidence":"High","gaps":["Mechanism by which export and oligomerization are mechanistically coupled not resolved","No structural model of the active region"]},{"year":2003,"claim":"Identified dynactin as a BEX3 partner and revealed species/context dependence of p75NTR coupling, while showing forced expression suppresses tumor growth in vivo.","evidence":"Yeast two-hybrid, co-IP, and stable transfection xenograft growth assays (CHO, MDA-MB-231)","pmids":["12739005"],"confidence":"Medium","gaps":["Negative p75NTR co-IP conflicts with earlier interaction data; cause unresolved","Mechanism of tumor suppression not defined","Functional relevance of dynactin binding untested"]},{"year":2004,"claim":"Connected BEX3 to additional pathways by demonstrating Smac/DIABLO binding that inhibits XIAP-mediated Smac ubiquitination and promotes TRAIL-induced apoptosis, and an OMP interaction able to relocalize OMP.","evidence":"Yeast two-hybrid/pulldown, domain mapping, co-IP, ubiquitination and apoptosis assays (MCF-7); phage display and chemical cross-linking for OMP","pmids":["15178455","12911636","15198671"],"confidence":"Medium","gaps":["Single-lab interaction data without reciprocal in vivo validation","Physiological context of OMP interaction not established"]},{"year":2004,"claim":"Localized BEX3 to perinuclear mitochondria undergoing DNA replication and defined sequence requirements (NES and CaaX box) for this targeting, linking it to cell growth.","evidence":"GFP-fusion deconvolution microscopy, NES/CaaX deletion mutagenesis, siRNA knockdown growth assay in F9 cells","pmids":["15563833"],"confidence":"Medium","gaps":["Functional role of mitochondrial localization not defined","Single cell line"]},{"year":2005,"claim":"Distinguished BEX3 from paralogs by its cytoplasmic localization and proteasomal turnover, and predicted a metal-binding histidine-rich domain.","evidence":"Subcellular fractionation/microscopy, proteasome inhibitor treatment, sequence analysis of rat Bex proteins","pmids":["15958283"],"confidence":"Low","gaps":["Metal binding predicted from sequence only, no direct binding assay","Single study"]},{"year":2006,"claim":"Implicated BEX3 in negative control of proliferation by showing it antagonizes DRG-1-driven cell-cycle progression.","evidence":"Yeast two-hybrid, co-IP with domain mapping, MTT proliferation and flow cytometry cell-cycle analysis","pmids":["16777077"],"confidence":"Medium","gaps":["Molecular mechanism of cell-cycle antagonism unresolved","Single lab"]},{"year":2007,"claim":"Identified hamartin (TSC1) as a constitutive BEX3 partner that protects it from proteasomal degradation, defining the upstream control of BEX3 abundance needed for apoptosis.","evidence":"Yeast two-hybrid, coiled-coil pulldown, co-IP, immunofluorescence in neurons/mouse brain, TSC1 siRNA with apoptosis readout","pmids":["17355907"],"confidence":"High","gaps":["Whether hamartin regulates BEX3's nuclear/transcriptional roles untested","Identity of the degrading E3 ligase unknown"]},{"year":2015,"claim":"Revealed a nuclear, transcription-factor-like function for BEX3, demonstrating dimerization-dependent shuttling and direct association with the trkA promoter to enhance TrkA expression and neuronal survival.","evidence":"qChIP, trkA promoter reporter assays, shRNA knockdown apoptosis/differentiation readouts in sensory neurons and PC12 cells","pmids":["25948268"],"confidence":"High","gaps":["Whether BEX3 binds DNA directly or via a cofactor not resolved","Other transcriptional targets not mapped"]},{"year":2015,"claim":"Resolved the biophysical nature of BEX3 as an intrinsically disordered protein that nonetheless forms a defined higher-order oligomer with a folded core, reconciling its adaptor versatility with structural constraints.","evidence":"SAXS, AFM, solution NMR, CD, fluorescence, partial proteolysis of recombinant BEX3; CD/bioinformatics across the Bex family","pmids":["26383250","25612294"],"confidence":"High","gaps":["No high-resolution structure of the oligomer","Disorder claim for the family rests on Bex1 CD data"]},{"year":2017,"claim":"Extended BEX3 function to cancer by showing it regulates OCT4 expression and modulates cisplatin resistance in nasopharyngeal carcinoma.","evidence":"siRNA and shRNA knockdown with OCT4 quantification and cisplatin sensitivity assays","pmids":["28083995"],"confidence":"Medium","gaps":["Mechanism linking BEX3 to OCT4 not defined","Single tumor type"]},{"year":2020,"claim":"Established a physiological in vivo requirement for Bex3 in interneuron development and hippocampal circuit function.","evidence":"Two murine Bex3 alleles with interneuron histology, hippocampal electrophysiology, and behavioral testing","pmids":["33100228"],"confidence":"Medium","gaps":["Molecular pathway underlying the neuronal phenotype not connected to BEX3's biochemical functions","Single study"]},{"year":null,"claim":"How BEX3's nuclear transcriptional activity, mitochondrial localization, apoptotic adaptor roles, and proliferation control are integrated into a single regulatory logic remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking subcellular pools to distinct outputs","No high-resolution structure of any BEX3 complex","DNA-binding mechanism at the trkA promoter unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,7,8]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,7]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6,8]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,9]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,9]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[9]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[9,13]}],"complexes":[],"partners":["NGFR","TSC1","DIABLO","DRG1","OMP","DCTN1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q00994","full_name":"Protein BEX3","aliases":["Brain-expressed X-linked protein 3","Nerve growth factor receptor-associated protein 1","Ovarian granulosa cell 13.0 kDa protein HGR74","p75NTR-associated cell death executor"],"length_aa":111,"mass_kda":13.0,"function":"May be a signaling adapter molecule involved in NGFR/p75NTR-mediated apoptosis induced by NGF. Plays a role in zinc-triggered neuronal death. In absence of reductive stress, acts as a pseudosubstrate for the CRL2(FEM1B) complex: associates with FEM1B via zinc, thereby preventing association between FEM1B and its substrates","subcellular_location":"Nucleus; Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/Q00994/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BEX3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/BEX3","total_profiled":1310},"omim":[{"mim_id":"300693","title":"BEX FAMILY MEMBER 5; BEX5","url":"https://www.omim.org/entry/300693"},{"mim_id":"300692","title":"BEX FAMILY MEMBER 4; BEX4","url":"https://www.omim.org/entry/300692"},{"mim_id":"300691","title":"BRAIN-EXPRESSED X-LINKED GENE 2; BEX2","url":"https://www.omim.org/entry/300691"},{"mim_id":"300690","title":"BRAIN-EXPRESSED X-LINKED GENE 1; BEX1","url":"https://www.omim.org/entry/300690"},{"mim_id":"300361","title":"NERVE GROWTH FACTOR RECEPTOR-ASSOCIATED PROTEIN 1; NGFRAP1","url":"https://www.omim.org/entry/300361"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"choroid plexus","ntpm":829.7}],"url":"https://www.proteinatlas.org/search/BEX3"},"hgnc":{"alias_symbol":["Bex","NADE","HGR74","Hero20","DXS6984E"],"prev_symbol":["NGFRAP1"]},"alphafold":{"accession":"Q00994","domains":[{"cath_id":"1.20.5","chopping":"64-98","consensus_level":"medium","plddt":88.314,"start":64,"end":98}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q00994","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q00994-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q00994-F1-predicted_aligned_error_v6.png","plddt_mean":64.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BEX3","jax_strain_url":"https://www.jax.org/strain/search?query=BEX3"},"sequence":{"accession":"Q00994","fasta_url":"https://rest.uniprot.org/uniprotkb/Q00994.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q00994/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q00994"}},"corpus_meta":[{"pmid":"10764727","id":"PMC_10764727","title":"NADE, a p75NTR-associated cell death executor, is involved in signal transduction mediated by the common neurotrophin receptor p75NTR.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10764727","citation_count":164,"is_preprint":false},{"pmid":"24549842","id":"PMC_24549842","title":"Metabolic and bactericidal effects of targeted suppression of NadD and NadE enzymes in mycobacteria.","date":"2014","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/24549842","citation_count":66,"is_preprint":false},{"pmid":"15958283","id":"PMC_15958283","title":"Characterization of the Bex gene family in humans, mice, and rats.","date":"2005","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/15958283","citation_count":64,"is_preprint":false},{"pmid":"11830582","id":"PMC_11830582","title":"Structure-function analysis of NADE: identification of regions that mediate nerve growth factor-induced apoptosis.","date":"2002","source":"The Journal of 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interaction of Smac with NADE promotes TRAIL-induced apoptosis.","date":"2004","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/15178455","citation_count":25,"is_preprint":false},{"pmid":"12399511","id":"PMC_12399511","title":"Bex, the Bacillus subtilis homolog of the essential Escherichia coli GTPase Era, is required for normal cell division and spore formation.","date":"2002","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/12399511","citation_count":25,"is_preprint":false},{"pmid":"12852261","id":"PMC_12852261","title":"Nerve growth factor-dependent regulation of NADE-induced apoptosis.","date":"2003","source":"Vitamins and hormones","url":"https://pubmed.ncbi.nlm.nih.gov/12852261","citation_count":24,"is_preprint":false},{"pmid":"12873743","id":"PMC_12873743","title":"Co-induction of p75(NTR) and the associated death executor NADE in degenerating hippocampal neurons after kainate-induced seizures in the 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Cell death was NGF-dependent and required both NADE and p75NTR co-expression; NADE alone was insufficient.\",\n      \"method\": \"Yeast two-hybrid screen, co-expression apoptosis assays in 293T/PC12/nnr5 cells and oligodendrocytes, dose-dependent recruitment assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction confirmed by yeast two-hybrid and functional cell-based assays, replicated across multiple cell lines (293T, PC12, nnr5, oligodendrocytes) in a single rigorous study\",\n      \"pmids\": [\"10764727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Mutational analysis of NADE (BEX3) defined that residues 41–71 are sufficient to induce apoptosis; the C-terminal regulatory region (residues 72–112) is required for NGF-dependent regulation. Mutations in the leucine-rich nuclear export signal (NES, residues 90–100) abolished nuclear export of NADE, its self-association, interaction with p75NTR, and NGF-dependent apoptosis. A dominant-negative fragment (residues 81–124) blocked NGF-induced apoptosis in oligodendrocytes.\",\n      \"method\": \"Truncation and point mutagenesis, nuclear export assays, co-immunoprecipitation, apoptosis assays in oligodendrocytes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis with multiple orthogonal functional readouts (localization, self-association, p75NTR binding, apoptosis) in a single rigorous study\",\n      \"pmids\": [\"11830582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NADE (BEX3) interacts with Smac/DIABLO; the interaction maps to the N-terminal region of Smac and the C-terminal region of NADE. Co-expression of NADE and Smac promotes TRAIL-induced apoptosis in MCF-7 cells, and their co-presence inhibits XIAP-mediated ubiquitination of Smac.\",\n      \"method\": \"Yeast two-hybrid/pulldown screen for Smac-binding proteins, co-immunoprecipitation, apoptosis assays, ubiquitination assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction mapped by domain deletion and confirmed by co-IP, functional consequence shown in cell-based assay, single lab\",\n      \"pmids\": [\"15178455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Human NADE (BEX3) was identified as a binding partner of dynactin by yeast two-hybrid screening; however, p75NTR did not co-immunoprecipitate with human NADE, and cells stably expressing human NADE did not respond to NGF or TNF. Forced NADE expression suppressed tumor growth in vivo (CHO and MDA-MB-231 xenografts) without affecting in vitro growth.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, stable transfection with in vivo xenograft growth assay\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid interaction with dynactin, negative co-IP result for p75NTR, in vivo tumor suppression, single lab\",\n      \"pmids\": [\"12739005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Bex (BEX3 ortholog) proteins were identified as interaction partners of olfactory marker protein (OMP); the interaction was confirmed by chemical cross-linking of recombinant OMP with a synthetic Bex-derived peptide, and by co-immunoprecipitation. Co-transfection of OMP with Bex results in some OMP appearing in the nucleus, suggesting Bex can alter OMP subcellular localization.\",\n      \"method\": \"Phage-display screening, chemical cross-linking, co-immunoprecipitation, co-transfection localization in HEK293 cells\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal binding assays (phage display, chemical cross-linking, co-IP) in a single study; functional consequence (nuclear relocalization of OMP) shown but not deeply characterized\",\n      \"pmids\": [\"12911636\", \"15198671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Bex3 localizes to perinuclear mitochondria undergoing active DNA replication in F9 teratocarcinoma cells, visualized as GFP fusion protein by deconvolution microscopy. Mitochondrial localization requires both the NES and the C-terminal CaaX box. siRNA-mediated reduction of Bex3 levels results in negligible cell growth.\",\n      \"method\": \"GFP fusion protein deconvolution microscopy, deletion mutagenesis of NES and CaaX motifs, siRNA knockdown with growth assay\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by live imaging with mutagenesis defining required sequences, and loss-of-function growth phenotype; single lab\",\n      \"pmids\": [\"15563833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Among Bex family members, rat Bex3 (BEX3 ortholog) localizes to the cytoplasm and is degraded by the proteasome, while rat Bex1 and Bex2 are not. Rat Bex3 protein can likely bind transition metals through a histidine-rich domain.\",\n      \"method\": \"Subcellular fractionation/microscopy of transfected cells, proteasome inhibitor treatment, sequence analysis of histidine-rich domain\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization and proteasome sensitivity shown in transfected cells, single study; metal-binding is predicted from sequence without direct binding assay\",\n      \"pmids\": [\"15958283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The TSC1 gene product hamartin interacts with NADE (BEX3); the interaction was confirmed by pulldown of endogenous NADE with the immobilized coiled-coil domain of hamartin, and by immunoprecipitation and immunofluorescence in neurons and mouse brain. Hamartin constitutively associates with NADE to prevent its proteasomal degradation; TSC1 siRNA knockdown reduces NADE levels and abolishes NGF-induced apoptosis in PC12h cells.\",\n      \"method\": \"Yeast two-hybrid, pulldown assay with immobilized coiled-coil domain, co-immunoprecipitation, immunofluorescence, siRNA knockdown with apoptosis readout\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — interaction confirmed by multiple orthogonal methods (pulldown, co-IP, immunofluorescence) in cells and in vivo tissue, with functional consequence (proteasomal stabilization and apoptosis) established\",\n      \"pmids\": [\"17355907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"DRG-1 (dopamine responsive gene-1) interacts with NADE (BEX3) in vivo and in vitro; the interaction maps to the N-terminal of DRG-1 and the C-terminal of NADE, and occurs in the cytoplasm. Stable expression of DRG-1 promotes cell proliferation, and this is suppressed by NADE overexpression. DRG-1 overexpression increases the S-phase population, implicating NADE in negative regulation of cell cycle progression.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, domain mapping, MTT proliferation assay, flow cytometry cell cycle analysis\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction confirmed by co-IP with domain mapping; functional antagonism shown by orthogonal proliferation and cell cycle assays; single lab\",\n      \"pmids\": [\"16777077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Bex3 dimerization and nuclear shuttling are required for transcriptional regulation of the trkA promoter. Bex3 associates with a 150 bp region immediately upstream of the trkA transcription start site (confirmed by qChIP). Bex3 enhances basal and NGF-induced trkA promoter activation. shRNA-mediated downregulation of Bex3 increases neuronal apoptosis in NGF-deprived sensory neurons and compromises NGF-induced PC12 differentiation.\",\n      \"method\": \"qChIP, trkA promoter reporter assays, shRNA knockdown with apoptosis and differentiation readouts in sensory neurons and PC12 cells\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct chromatin association confirmed by qChIP, functional consequence shown by orthogonal reporter assays and loss-of-function in primary neurons and PC12 cells; multiple readouts in a single rigorous study\",\n      \"pmids\": [\"25948268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Biophysical characterization of recombinant BEX3 by SAXS, AFM, solution NMR, partial proteinase K digestion, circular dichroism, and fluorescence revealed that BEX3 forms a specific higher-order oligomer consistent with a globular molecule, contains ~31% α-helix and ~20% β-strand, has partially folded regions near N- and C-termini, and a proteolysis-resistant core around residues 55–120.\",\n      \"method\": \"Small angle X-ray scattering (SAXS), atomic force microscopy, solution NMR, circular dichroism, fluorescence spectroscopy, partial proteinase K digestion of recombinant protein\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biophysical methods on recombinant protein providing consistent structural characterization\",\n      \"pmids\": [\"26383250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Bex proteins (including BEX3) are intrinsically disordered proteins (IDPs), confirmed by circular dichroism spectroscopy of purified Bex1 expressed in E. coli, and bioinformatics analyses showing conserved long disordered regions across all family members.\",\n      \"method\": \"Bioinformatics disorder prediction, circular dichroism spectroscopy of recombinant Bex1\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — CD spectroscopy performed on Bex1 (not BEX3 directly), bioinformatics extended to BEX3; single study, indirect evidence for BEX3 specifically\",\n      \"pmids\": [\"25612294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BEX3 knockdown via siRNA in nasopharyngeal carcinoma (NPC) cells significantly reduced OCT4 expression, and shRNA-mediated BEX3 suppression increased NPC cell sensitivity to cisplatin, establishing BEX3 as a regulator of OCT4 expression and cisplatin resistance in NPC.\",\n      \"method\": \"siRNA knockdown with OCT4 protein quantification, shRNA stable knockdown with cisplatin sensitivity assay\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal loss-of-function approaches with defined molecular (OCT4) and cellular (cisplatin resistance) readouts; single lab\",\n      \"pmids\": [\"28083995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Two different murine Bex3 alleles result in reduced interneuron number and hippocampal electrophysiological imbalance, with distinct behavioral phenotypes, establishing Bex3 as required for higher brain functions including interneuron development and hippocampal circuit function.\",\n      \"method\": \"Murine Bex3 allele analysis, histological interneuron quantification, hippocampal electrophysiology, behavioral testing\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined morphological, electrophysiological, and behavioral readouts; single study\",\n      \"pmids\": [\"33100228\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BEX3 (NADE) is an intrinsically disordered, higher-order oligomeric adaptor protein that binds the death domain of p75NTR via a core apoptosis-executing region (residues 41–71), requires a leucine-rich NES (residues 90–100) for nuclear export, self-association, and p75NTR interaction, and mediates NGF-dependent caspase-2/3 activation; it is stabilized against proteasomal degradation by hamartin (TSC1), interacts with Smac/DIABLO to inhibit XIAP-mediated Smac ubiquitination and promote TRAIL-induced apoptosis, interacts with DRG-1 to negatively regulate cell proliferation, shuttles to the nucleus where it binds the trkA promoter to enhance TrkA expression and NGF-dependent neuronal survival/differentiation, localizes to replicating perinuclear mitochondria via its NES and CaaX box, and is required for normal interneuron number and hippocampal circuit function in vivo.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BEX3 (NADE) is an intrinsically disordered, higher-order oligomeric adaptor protein that couples neurotrophin receptor signaling to apoptotic and transcriptional outputs [#0, #10]. It was first defined as a p75NTR death-domain binding partner whose co-expression drives NGF-dependent caspase-2/3 activation and DNA fragmentation, with an apoptosis-executing core in residues 41\\u201371 and a C-terminal regulatory region (72\\u2013112) governing NGF dependence [#0, #1]. A leucine-rich nuclear export signal (residues 90\\u2013100) is required for nuclear export, self-association, and p75NTR binding, and biophysical analysis maps a proteolysis-resistant globular core to residues ~55\\u2013120 flanked by partially folded termini [#1, #10]. BEX3 also acts in the nucleus as a transcriptional regulator: dimerization-dependent shuttling allows it to associate with a region immediately upstream of the trkA transcription start site and enhance basal and NGF-induced TrkA expression, promoting neuronal survival and differentiation [#9]. Its abundance is controlled by the proteasome, and the TSC1 product hamartin constitutively binds BEX3 to prevent its degradation, a stabilization required for NGF-induced apoptosis [#7]. BEX3 further engages Smac/DIABLO to block XIAP-mediated Smac ubiquitination and promote TRAIL-induced apoptosis, and antagonizes DRG-1-driven proliferation [#2, #8]. In vivo, two murine Bex3 alleles produce reduced interneuron number and hippocampal circuit imbalance, establishing a requirement for normal brain function [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established BEX3/NADE as a death-domain effector that links p75NTR to the apoptotic machinery, answering how the receptor triggers cell death.\",\n      \"evidence\": \"Yeast two-hybrid against p75NTR plus co-expression apoptosis assays in 293T, PC12, nnr5 and oligodendrocytes\",\n      \"pmids\": [\"10764727\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the structural basis or the BEX3 residues mediating the interaction\", \"Downstream of caspase activation left unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Mapped the functional architecture of BEX3, showing distinct apoptosis-executing and regulatory regions and that a leucine-rich NES couples export, self-association, and p75NTR binding to apoptosis.\",\n      \"evidence\": \"Truncation/point mutagenesis with nuclear export, co-IP, and apoptosis readouts in oligodendrocytes\",\n      \"pmids\": [\"11830582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which export and oligomerization are mechanistically coupled not resolved\", \"No structural model of the active region\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified dynactin as a BEX3 partner and revealed species/context dependence of p75NTR coupling, while showing forced expression suppresses tumor growth in vivo.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, and stable transfection xenograft growth assays (CHO, MDA-MB-231)\",\n      \"pmids\": [\"12739005\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative p75NTR co-IP conflicts with earlier interaction data; cause unresolved\", \"Mechanism of tumor suppression not defined\", \"Functional relevance of dynactin binding untested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Connected BEX3 to additional pathways by demonstrating Smac/DIABLO binding that inhibits XIAP-mediated Smac ubiquitination and promotes TRAIL-induced apoptosis, and an OMP interaction able to relocalize OMP.\",\n      \"evidence\": \"Yeast two-hybrid/pulldown, domain mapping, co-IP, ubiquitination and apoptosis assays (MCF-7); phage display and chemical cross-linking for OMP\",\n      \"pmids\": [\"15178455\", \"12911636\", \"15198671\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab interaction data without reciprocal in vivo validation\", \"Physiological context of OMP interaction not established\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Localized BEX3 to perinuclear mitochondria undergoing DNA replication and defined sequence requirements (NES and CaaX box) for this targeting, linking it to cell growth.\",\n      \"evidence\": \"GFP-fusion deconvolution microscopy, NES/CaaX deletion mutagenesis, siRNA knockdown growth assay in F9 cells\",\n      \"pmids\": [\"15563833\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of mitochondrial localization not defined\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Distinguished BEX3 from paralogs by its cytoplasmic localization and proteasomal turnover, and predicted a metal-binding histidine-rich domain.\",\n      \"evidence\": \"Subcellular fractionation/microscopy, proteasome inhibitor treatment, sequence analysis of rat Bex proteins\",\n      \"pmids\": [\"15958283\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Metal binding predicted from sequence only, no direct binding assay\", \"Single study\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Implicated BEX3 in negative control of proliferation by showing it antagonizes DRG-1-driven cell-cycle progression.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP with domain mapping, MTT proliferation and flow cytometry cell-cycle analysis\",\n      \"pmids\": [\"16777077\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of cell-cycle antagonism unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified hamartin (TSC1) as a constitutive BEX3 partner that protects it from proteasomal degradation, defining the upstream control of BEX3 abundance needed for apoptosis.\",\n      \"evidence\": \"Yeast two-hybrid, coiled-coil pulldown, co-IP, immunofluorescence in neurons/mouse brain, TSC1 siRNA with apoptosis readout\",\n      \"pmids\": [\"17355907\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether hamartin regulates BEX3's nuclear/transcriptional roles untested\", \"Identity of the degrading E3 ligase unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed a nuclear, transcription-factor-like function for BEX3, demonstrating dimerization-dependent shuttling and direct association with the trkA promoter to enhance TrkA expression and neuronal survival.\",\n      \"evidence\": \"qChIP, trkA promoter reporter assays, shRNA knockdown apoptosis/differentiation readouts in sensory neurons and PC12 cells\",\n      \"pmids\": [\"25948268\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether BEX3 binds DNA directly or via a cofactor not resolved\", \"Other transcriptional targets not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved the biophysical nature of BEX3 as an intrinsically disordered protein that nonetheless forms a defined higher-order oligomer with a folded core, reconciling its adaptor versatility with structural constraints.\",\n      \"evidence\": \"SAXS, AFM, solution NMR, CD, fluorescence, partial proteolysis of recombinant BEX3; CD/bioinformatics across the Bex family\",\n      \"pmids\": [\"26383250\", \"25612294\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of the oligomer\", \"Disorder claim for the family rests on Bex1 CD data\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended BEX3 function to cancer by showing it regulates OCT4 expression and modulates cisplatin resistance in nasopharyngeal carcinoma.\",\n      \"evidence\": \"siRNA and shRNA knockdown with OCT4 quantification and cisplatin sensitivity assays\",\n      \"pmids\": [\"28083995\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking BEX3 to OCT4 not defined\", \"Single tumor type\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established a physiological in vivo requirement for Bex3 in interneuron development and hippocampal circuit function.\",\n      \"evidence\": \"Two murine Bex3 alleles with interneuron histology, hippocampal electrophysiology, and behavioral testing\",\n      \"pmids\": [\"33100228\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathway underlying the neuronal phenotype not connected to BEX3's biochemical functions\", \"Single study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How BEX3's nuclear transcriptional activity, mitochondrial localization, apoptotic adaptor roles, and proliferation control are integrated into a single regulatory logic remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking subcellular pools to distinct outputs\", \"No high-resolution structure of any BEX3 complex\", \"DNA-binding mechanism at the trkA promoter unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 7, 8]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [9, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NGFR\", \"TSC1\", \"DIABLO\", \"DRG1\", \"OMP\", \"DCTN1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}