{"gene":"ADGRB3","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2011,"finding":"All four C1q-like proteins (C1ql1-C1ql4) bind with high affinity to the extracellular thrombospondin-repeat (TSR) domain of BAI3, mediated by the globular C1q domains of the C1ql proteins; this interaction regulates synapse density in cultured neurons.","method":"Biochemical binding assay (pulldown), neuronal synapse density quantification, competitive inhibition with TSR fragment","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal biochemical methods with functional validation, highly cited foundational paper","pmids":["21262840"],"is_preprint":false},{"year":2014,"finding":"BAI3 acts as a cell-surface receptor that directly interacts with ELMO proteins to promote myoblast fusion via the ELMO/DOCK1/Rac pathway; BAI3 mutants deficient in ELMO binding cannot rescue myoblast fusion defects, and embryonic expression of ELMO-binding-deficient BAI3 blocks fusion in vivo.","method":"Co-immunoprecipitation, loss-of-function (siRNA/dominant negative), in vivo rescue experiments in mouse embryos","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, loss-of-function with defined cellular phenotype, in vivo validation, replicated in subsequent studies","pmids":["24567399"],"is_preprint":false},{"year":2013,"finding":"BAI3 controls dendritic arborization growth and branching in neurons via activation of RhoGTPase Rac1 and direct binding to ELMO1; knockdown or overexpression of dominant-negative BAI3 in cultured neurons and Purkinje cells in vivo confirmed this role.","method":"shRNA knockdown, overexpression, transgenic mice, lentivirus-driven knockdown, Rac1 activation assay","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KD + OE + in vivo), defined pathway placement via Rac1/ELMO1","pmids":["23628982"],"is_preprint":false},{"year":2015,"finding":"The C1QL1–BAI3 signaling pathway controls the synaptic connectivity and territory of climbing fiber and parallel fiber afferents on cerebellar Purkinje cells; restricted expression of C1QL1 in inferior olivary neurons ensures proper climbing fiber synaptic territory.","method":"Genetic knockdown/knockout in mice, electrophysiology, immunohistochemistry, in vivo synapse quantification","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — multiple in vivo genetic approaches with defined synaptic phenotypes, replicated across labs","pmids":["25660030"],"is_preprint":false},{"year":2018,"finding":"Stabilin-2 binds BAI3 and activates its GPCR activity; activated heterotrimeric G-proteins recruit ELMO proteins to the membrane, which are then stabilized on BAI3 via direct interaction, promoting myoblast fusion. C1q-like proteins (C1ql1-4) repress BAI3-mediated fusion by interacting with BAI3.","method":"Proteomic/mass spectrometry interactome, GPCR activation assay (BRET), Co-IP, BAI3 knockout mice, cardiotoxin muscle regeneration model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — GPCR activity assay, proteomic identification, in vivo KO phenotype, multiple orthogonal methods","pmids":["30367035"],"is_preprint":false},{"year":2018,"finding":"BAI3 mediates inhibition of insulin secretion by C1QL3 in pancreatic β-cells primarily through regulation of cAMP signaling; BAI3 knockdown increased glucose-stimulated insulin secretion, and the soluble C1ql3-binding TSR fragment of BAI3 blocked C1ql3's inhibitory effects.","method":"siRNA knockdown in INS1(832/13) cells, insulin secretion assay, cAMP measurement, competitive inhibition with BAI3 fragment","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with defined phenotype and pathway, single lab","pmids":["30228187"],"is_preprint":false},{"year":2021,"finding":"C1QL3 mediates formation of a novel trans-synaptic adhesion complex by bridging ADGRB3/BAI3 (postsynaptic) with neuronal pentraxins NPTX1 and NPTXR (presynaptically co-expressed); this complex was identified by in vivo interactome analysis.","method":"In vivo interactome/co-immunoprecipitation, cell-cell adhesion assay, single-cell RNA-seq co-expression analysis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP in vivo plus cell adhesion assay, single lab","pmids":["33337553"],"is_preprint":false},{"year":2023,"finding":"C1ql1–BAI3 signaling is required for climbing fiber synapse formation on mature Purkinje cells; overexpression of C1ql1 or BAI3 caused CF transverse branches to form synapses on distal dendrites, and the effect of GluD2 knockout-induced reinnervation was absent in BAI3 knockout mice, placing BAI3 downstream of GluD2 in CF synaptogenesis.","method":"Electrophysiology, Ca2+-imaging, immunohistochemistry, viral overexpression, genetic epistasis (BAI3 KO × GluD2 KO double mutant)","journal":"Molecular brain","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with multiple readouts, orthogonal methods","pmids":["37488606"],"is_preprint":false},{"year":2019,"finding":"BAI3 functions as a receptor in Leydig cells that participates in C1QL4-induced steroidogenesis; BAI3 knockdown reduced StAR expression and altered ERK1/2 and cAMP signaling, though C1QL4 also activates an unidentified additional receptor via ERK1/2 and cAMP.","method":"siRNA knockdown in TM3 Leydig cells, testosterone/StAR expression assay, signaling pathway analysis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2-3 — clean KD with defined molecular phenotype, single lab","pmids":["30608882"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structure of C1ql3–BAI3 complex at 2.8 Å resolution reveals a hexameric configuration: a central C1ql3 homotrimer captures three BAI3 molecules fitting into grooves between trimeric C1q domains, with Ca2+-mediated interactions; mutagenesis of contact residues confirmed essential binding residues.","method":"Single-particle cryo-EM (2.8 Å), mutagenesis, cell surface staining","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1 — high-resolution cryo-EM structure with mutagenesis validation","pmids":["40316654"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structure reveals that the trimeric gC1q domain of C1ql1 undergoes calcium-modulated domain-swapping to form a hexamer that binds the extended CUB domain of BAI3; full-length C1ql1 further assembles into linear clusters to accumulate BAI3 on the plasma membrane, supporting synapse maintenance in vivo.","method":"Cryo-EM, biochemical analysis, molecular dynamics simulation, cellular and in vivo studies","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure with in vitro and in vivo functional validation","pmids":["41372137"],"is_preprint":false},{"year":2023,"finding":"CRISPR/Cas9 knockout mice lacking full-length BAI3 display reduced brain and body weights and deficits in social interaction, confirming in vivo roles for BAI3 in brain development and social behavior.","method":"CRISPR/Cas9 knockout, Western blot, behavioral assays","journal":"Basic & clinical pharmacology & toxicology","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined behavioral phenotype, single lab","pmids":["37337931"],"is_preprint":false},{"year":2023,"finding":"Whole-body BAI3 knockout mice show increased energy expenditure and reduced body weight associated with enhanced adaptive thermogenesis, with upregulated thermogenic gene expression (Ucp1, Pgc1α, Prdm16, Elov3) in brown adipose tissue.","method":"CRISPR/Cas9 whole-body KO, CLAMS metabolic monitoring, qRT-PCR, quantitative MRI body composition","journal":"Metabolites","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined metabolic phenotype, single lab","pmids":["37367869"],"is_preprint":false}],"current_model":"ADGRB3/BAI3 is a brain-enriched adhesion-GPCR whose extracellular TSR/CUB domain binds C1q-like proteins (C1ql1–4) in a calcium-dependent hexameric configuration (resolved by cryo-EM); ligand binding regulates synapse formation, climbing fiber connectivity, and dendritic morphogenesis, while Stabilin-2 activates BAI3's GPCR activity to recruit ELMO proteins via heterotrimeric G-proteins, coupling BAI3 to the ELMO/DOCK1/Rac1 pathway that drives both myoblast fusion and actin cytoskeleton remodeling in neurons; additionally, BAI3 mediates C1QL3-dependent inhibition of insulin secretion via cAMP signaling and regulates adaptive thermogenesis in vivo."},"narrative":{"teleology":[{"year":2011,"claim":"Identification of C1ql1–4 as high-affinity ligands for BAI3's TSR domain established ADGRB3 as a synapse-regulating receptor with defined extracellular binding partners, answering the long-standing question of what ligands engage adhesion-GPCRs of this subfamily.","evidence":"Biochemical pulldown with purified TSR fragments and neuronal synapse density quantification in cultured neurons","pmids":["21262840"],"confidence":"High","gaps":["Structural basis of C1ql–BAI3 interaction unresolved","Downstream signaling pathway from C1ql binding unknown","In vivo synapse phenotype not yet tested"]},{"year":2013,"claim":"Demonstrating that BAI3 drives dendritic arborization through ELMO1/Rac1 placed the receptor within a defined intracellular signaling cascade controlling neuronal morphogenesis.","evidence":"shRNA knockdown, dominant-negative overexpression in cultured neurons and Purkinje cells in vivo, Rac1 activation assay","pmids":["23628982"],"confidence":"High","gaps":["Whether ELMO1 binding is direct or requires intermediary activation unknown","Relative contribution of BAI3 versus other Rac1 activators in dendritogenesis untested"]},{"year":2014,"claim":"Showing that BAI3 directly recruits ELMO proteins to promote DOCK1/Rac1-dependent myoblast fusion extended BAI3's function beyond neurons and established it as a bona fide fusogenic receptor.","evidence":"Reciprocal co-immunoprecipitation, ELMO-binding-deficient BAI3 mutants fail to rescue fusion in vivo in mouse embryos","pmids":["24567399"],"confidence":"High","gaps":["Mechanism of BAI3 GPCR activation during fusion unclear","Identity of the extracellular cue triggering BAI3-mediated fusion in muscle unknown"]},{"year":2015,"claim":"Genetic evidence that C1QL1–BAI3 signaling specifies climbing fiber synaptic territory on Purkinje cells answered how this ligand–receptor pair functions in circuit-level synapse organization in vivo.","evidence":"Knockout/knockdown in mice with electrophysiology and immunohistochemistry quantifying climbing fiber and parallel fiber territories","pmids":["25660030"],"confidence":"High","gaps":["Intracellular signaling downstream of C1QL1–BAI3 at synapses uncharacterized","Whether BAI3 GPCR activity is engaged at these synapses untested"]},{"year":2018,"claim":"Discovery that Stabilin-2 activates BAI3's GPCR function and that heterotrimeric G-proteins recruit ELMO to the membrane resolved how BAI3 couples GPCR signaling to cytoskeletal remodeling; C1ql proteins were shown to oppose this pathway, revealing a dual regulatory logic.","evidence":"BRET-based GPCR activation assay, proteomic/mass spectrometry interactome, BAI3 knockout mice with cardiotoxin muscle regeneration","pmids":["30367035"],"confidence":"High","gaps":["Which Gα subunit mediates ELMO recruitment not identified","Whether Stabilin-2 activates BAI3 in neurons unknown"]},{"year":2018,"claim":"BAI3 was established as a functional receptor for C1QL3 in pancreatic β-cells, mediating inhibition of glucose-stimulated insulin secretion through cAMP, extending BAI3 biology to metabolic regulation.","evidence":"siRNA knockdown in INS1(832/13) cells, insulin secretion and cAMP measurement, competitive inhibition with soluble TSR fragment","pmids":["30228187"],"confidence":"Medium","gaps":["Downstream effectors coupling BAI3 to cAMP in β-cells unidentified","In vivo validation of BAI3-dependent insulin regulation absent","Single-lab finding"]},{"year":2019,"claim":"BAI3 was implicated in C1QL4-driven steroidogenesis in Leydig cells, broadening the tissue repertoire of BAI3–C1ql signaling to endocrine function.","evidence":"siRNA knockdown in TM3 Leydig cells, StAR expression and ERK1/2/cAMP signaling analysis","pmids":["30608882"],"confidence":"Medium","gaps":["An additional unidentified receptor also contributes to C1QL4 signaling","In vivo relevance in steroidogenesis untested","Single-lab finding"]},{"year":2021,"claim":"Identification of a trans-synaptic complex in which C1QL3 bridges postsynaptic BAI3 to presynaptic neuronal pentraxins (NPTX1/NPTXR) revealed a higher-order adhesion architecture at synapses.","evidence":"In vivo co-immunoprecipitation, cell-cell adhesion assay, single-cell RNA-seq co-expression analysis","pmids":["33337553"],"confidence":"Medium","gaps":["Functional consequence of this trans-synaptic complex on synapse strength or specificity untested","Structural basis of pentameric pentraxin–trimeric C1ql interaction unknown","Single-lab finding"]},{"year":2023,"claim":"Genetic epistasis placing BAI3 downstream of GluD2 in climbing fiber synaptogenesis on mature Purkinje cells clarified the signaling hierarchy controlling cerebellar synapse formation.","evidence":"BAI3 KO × GluD2 KO double-mutant mice, electrophysiology, calcium imaging, viral overexpression","pmids":["37488606"],"confidence":"High","gaps":["Molecular link between GluD2 and BAI3 activation unresolved","Whether the epistasis reflects a shared pathway or parallel convergence unclear"]},{"year":2023,"claim":"BAI3 knockout mice displayed reduced brain/body weight, social interaction deficits, increased energy expenditure, and enhanced adaptive thermogenesis, establishing BAI3 as a pleiotropic regulator of brain development and whole-body metabolism in vivo.","evidence":"CRISPR/Cas9 whole-body KO mice, behavioral assays, CLAMS metabolic monitoring, qRT-PCR of thermogenic genes in BAT","pmids":["37337931","37367869"],"confidence":"Medium","gaps":["Cell-type-specific contributions (neuronal vs. adipocyte) not dissected","Molecular pathway linking BAI3 to thermogenic gene regulation unknown","Both studies from a single lab"]},{"year":2025,"claim":"Cryo-EM structures of C1ql1–BAI3 and C1ql3–BAI3 complexes at near-atomic resolution revealed a hexameric architecture with calcium-dependent domain-swapping in C1ql trimers capturing BAI3 CUB domains, and demonstrated that full-length C1ql1 forms linear clusters that accumulate BAI3 on the membrane to support synapse maintenance.","evidence":"Single-particle cryo-EM at 2.8 Å (C1ql3–BAI3) and complementary resolution (C1ql1–BAI3), mutagenesis of contact residues, molecular dynamics, in vivo synapse studies","pmids":["40316654","41372137"],"confidence":"High","gaps":["Structure of full-length BAI3 including 7TM domain not resolved","How ligand-induced clustering triggers GPCR activation mechanistically remains unknown"]},{"year":null,"claim":"The mechanism by which extracellular C1ql binding or Stabilin-2 engagement transmits conformational change through BAI3's GAIN/7TM domain to activate heterotrimeric G-proteins, and how this couples to distinct downstream pathways (Rac1 vs. cAMP) in different tissues, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of full-length BAI3 with 7TM domain available","G-protein coupling specificity (Gα identity) not determined","Tissue-specific switching between ELMO/Rac1 and cAMP pathways unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,4,5,8]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,4,9,10]}],"pathway":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4,5,8]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[3,7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,3,7,11]}],"complexes":["C1ql–BAI3 hexameric complex","C1QL3–BAI3–NPTX1/NPTXR trans-synaptic complex"],"partners":["C1QL1","C1QL3","C1QL4","ELMO1","DOCK1","STAB2","NPTX1","NPTXR"],"other_free_text":[]},"mechanistic_narrative":"ADGRB3 (BAI3) is a brain-enriched adhesion G-protein-coupled receptor that transduces extracellular ligand signals into cytoskeletal remodeling, synapse organization, and metabolic regulation across multiple tissues. Its extracellular thrombospondin-repeat (TSR) and CUB domains bind C1q-like proteins (C1ql1–4) in a calcium-dependent hexameric configuration—resolved by cryo-EM—where a C1ql trimer captures three BAI3 molecules, enabling clustering at the plasma membrane to regulate synapse density, climbing fiber connectivity on cerebellar Purkinje cells, and dendritic arborization via the ELMO1/DOCK1/Rac1 pathway [PMID:21262840, PMID:40316654, PMID:41372137, PMID:25660030, PMID:23628982]. Stabilin-2 activates BAI3's GPCR signaling through heterotrimeric G-proteins, which recruit ELMO to the membrane for DOCK1/Rac1-dependent myoblast fusion, while C1ql proteins antagonize this fusogenic activity [PMID:30367035]. Beyond the nervous system, BAI3 mediates C1QL3-dependent inhibition of insulin secretion via cAMP signaling in pancreatic β-cells, participates in C1QL4-induced steroidogenesis in Leydig cells, and restrains adaptive thermogenesis in brown adipose tissue, as whole-body knockout mice exhibit increased energy expenditure and upregulated thermogenic gene expression [PMID:30228187, PMID:30608882, PMID:37367869]."},"prefetch_data":{"uniprot":{"accession":"O60242","full_name":"Adhesion G protein-coupled receptor B3","aliases":["Brain-specific angiogenesis inhibitor 3"],"length_aa":1522,"mass_kda":171.5,"function":"Receptor that plays a role in the regulation of synaptogenesis and dendritic spine formation at least partly via interaction with ELMO1 and RAC1 activity (By similarity). Promotes myoblast fusion through ELMO/DOCK1 (PubMed:24567399)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/O60242/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADGRB3","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ADGRB3","total_profiled":1310},"omim":[{"mim_id":"616945","title":"CLAVESIN 2; CLVS2","url":"https://www.omim.org/entry/616945"},{"mim_id":"602684","title":"ADHESION G PROTEIN-COUPLED RECEPTOR B3; ADGRB3","url":"https://www.omim.org/entry/602684"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":28.2},{"tissue":"pituitary gland","ntpm":21.3}],"url":"https://www.proteinatlas.org/search/ADGRB3"},"hgnc":{"alias_symbol":["KIAA0550"],"prev_symbol":["BAI3"]},"alphafold":{"accession":"O60242","domains":[{"cath_id":"-","chopping":"41-137_152-198","consensus_level":"high","plddt":55.1384,"start":41,"end":198},{"cath_id":"4.10.1240.10","chopping":"516-562","consensus_level":"medium","plddt":92.3719,"start":516,"end":562},{"cath_id":"1.25.40.610","chopping":"565-669","consensus_level":"medium","plddt":91.703,"start":565,"end":669},{"cath_id":"2.60.220.50","chopping":"693-867","consensus_level":"medium","plddt":86.7769,"start":693,"end":867},{"cath_id":"1.20.1070.10","chopping":"881-1049_1090-1161","consensus_level":"high","plddt":79.4274,"start":881,"end":1161}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60242","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60242-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60242-F1-predicted_aligned_error_v6.png","plddt_mean":63.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADGRB3","jax_strain_url":"https://www.jax.org/strain/search?query=ADGRB3"},"sequence":{"accession":"O60242","fasta_url":"https://rest.uniprot.org/uniprotkb/O60242.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60242/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60242"}},"corpus_meta":[{"pmid":"21262840","id":"PMC_21262840","title":"The 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Disease","date":"2024-08-10","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.10.607452","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14966,"output_tokens":2977,"usd":0.044776},"stage2":{"model":"claude-opus-4-6","input_tokens":6370,"output_tokens":3118,"usd":0.1647},"total_usd":0.209476,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"All four C1q-like proteins (C1ql1-C1ql4) bind with high affinity to the extracellular thrombospondin-repeat (TSR) domain of BAI3, mediated by the globular C1q domains of the C1ql proteins; this interaction regulates synapse density in cultured neurons.\",\n      \"method\": \"Biochemical binding assay (pulldown), neuronal synapse density quantification, competitive inhibition with TSR fragment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal biochemical methods with functional validation, highly cited foundational paper\",\n      \"pmids\": [\"21262840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BAI3 acts as a cell-surface receptor that directly interacts with ELMO proteins to promote myoblast fusion via the ELMO/DOCK1/Rac pathway; BAI3 mutants deficient in ELMO binding cannot rescue myoblast fusion defects, and embryonic expression of ELMO-binding-deficient BAI3 blocks fusion in vivo.\",\n      \"method\": \"Co-immunoprecipitation, loss-of-function (siRNA/dominant negative), in vivo rescue experiments in mouse embryos\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, loss-of-function with defined cellular phenotype, in vivo validation, replicated in subsequent studies\",\n      \"pmids\": [\"24567399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BAI3 controls dendritic arborization growth and branching in neurons via activation of RhoGTPase Rac1 and direct binding to ELMO1; knockdown or overexpression of dominant-negative BAI3 in cultured neurons and Purkinje cells in vivo confirmed this role.\",\n      \"method\": \"shRNA knockdown, overexpression, transgenic mice, lentivirus-driven knockdown, Rac1 activation assay\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KD + OE + in vivo), defined pathway placement via Rac1/ELMO1\",\n      \"pmids\": [\"23628982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The C1QL1–BAI3 signaling pathway controls the synaptic connectivity and territory of climbing fiber and parallel fiber afferents on cerebellar Purkinje cells; restricted expression of C1QL1 in inferior olivary neurons ensures proper climbing fiber synaptic territory.\",\n      \"method\": \"Genetic knockdown/knockout in mice, electrophysiology, immunohistochemistry, in vivo synapse quantification\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vivo genetic approaches with defined synaptic phenotypes, replicated across labs\",\n      \"pmids\": [\"25660030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Stabilin-2 binds BAI3 and activates its GPCR activity; activated heterotrimeric G-proteins recruit ELMO proteins to the membrane, which are then stabilized on BAI3 via direct interaction, promoting myoblast fusion. C1q-like proteins (C1ql1-4) repress BAI3-mediated fusion by interacting with BAI3.\",\n      \"method\": \"Proteomic/mass spectrometry interactome, GPCR activation assay (BRET), Co-IP, BAI3 knockout mice, cardiotoxin muscle regeneration model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — GPCR activity assay, proteomic identification, in vivo KO phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"30367035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BAI3 mediates inhibition of insulin secretion by C1QL3 in pancreatic β-cells primarily through regulation of cAMP signaling; BAI3 knockdown increased glucose-stimulated insulin secretion, and the soluble C1ql3-binding TSR fragment of BAI3 blocked C1ql3's inhibitory effects.\",\n      \"method\": \"siRNA knockdown in INS1(832/13) cells, insulin secretion assay, cAMP measurement, competitive inhibition with BAI3 fragment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined phenotype and pathway, single lab\",\n      \"pmids\": [\"30228187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"C1QL3 mediates formation of a novel trans-synaptic adhesion complex by bridging ADGRB3/BAI3 (postsynaptic) with neuronal pentraxins NPTX1 and NPTXR (presynaptically co-expressed); this complex was identified by in vivo interactome analysis.\",\n      \"method\": \"In vivo interactome/co-immunoprecipitation, cell-cell adhesion assay, single-cell RNA-seq co-expression analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP in vivo plus cell adhesion assay, single lab\",\n      \"pmids\": [\"33337553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"C1ql1–BAI3 signaling is required for climbing fiber synapse formation on mature Purkinje cells; overexpression of C1ql1 or BAI3 caused CF transverse branches to form synapses on distal dendrites, and the effect of GluD2 knockout-induced reinnervation was absent in BAI3 knockout mice, placing BAI3 downstream of GluD2 in CF synaptogenesis.\",\n      \"method\": \"Electrophysiology, Ca2+-imaging, immunohistochemistry, viral overexpression, genetic epistasis (BAI3 KO × GluD2 KO double mutant)\",\n      \"journal\": \"Molecular brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple readouts, orthogonal methods\",\n      \"pmids\": [\"37488606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BAI3 functions as a receptor in Leydig cells that participates in C1QL4-induced steroidogenesis; BAI3 knockdown reduced StAR expression and altered ERK1/2 and cAMP signaling, though C1QL4 also activates an unidentified additional receptor via ERK1/2 and cAMP.\",\n      \"method\": \"siRNA knockdown in TM3 Leydig cells, testosterone/StAR expression assay, signaling pathway analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — clean KD with defined molecular phenotype, single lab\",\n      \"pmids\": [\"30608882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structure of C1ql3–BAI3 complex at 2.8 Å resolution reveals a hexameric configuration: a central C1ql3 homotrimer captures three BAI3 molecules fitting into grooves between trimeric C1q domains, with Ca2+-mediated interactions; mutagenesis of contact residues confirmed essential binding residues.\",\n      \"method\": \"Single-particle cryo-EM (2.8 Å), mutagenesis, cell surface staining\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution cryo-EM structure with mutagenesis validation\",\n      \"pmids\": [\"40316654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structure reveals that the trimeric gC1q domain of C1ql1 undergoes calcium-modulated domain-swapping to form a hexamer that binds the extended CUB domain of BAI3; full-length C1ql1 further assembles into linear clusters to accumulate BAI3 on the plasma membrane, supporting synapse maintenance in vivo.\",\n      \"method\": \"Cryo-EM, biochemical analysis, molecular dynamics simulation, cellular and in vivo studies\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure with in vitro and in vivo functional validation\",\n      \"pmids\": [\"41372137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CRISPR/Cas9 knockout mice lacking full-length BAI3 display reduced brain and body weights and deficits in social interaction, confirming in vivo roles for BAI3 in brain development and social behavior.\",\n      \"method\": \"CRISPR/Cas9 knockout, Western blot, behavioral assays\",\n      \"journal\": \"Basic & clinical pharmacology & toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined behavioral phenotype, single lab\",\n      \"pmids\": [\"37337931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Whole-body BAI3 knockout mice show increased energy expenditure and reduced body weight associated with enhanced adaptive thermogenesis, with upregulated thermogenic gene expression (Ucp1, Pgc1α, Prdm16, Elov3) in brown adipose tissue.\",\n      \"method\": \"CRISPR/Cas9 whole-body KO, CLAMS metabolic monitoring, qRT-PCR, quantitative MRI body composition\",\n      \"journal\": \"Metabolites\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined metabolic phenotype, single lab\",\n      \"pmids\": [\"37367869\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADGRB3/BAI3 is a brain-enriched adhesion-GPCR whose extracellular TSR/CUB domain binds C1q-like proteins (C1ql1–4) in a calcium-dependent hexameric configuration (resolved by cryo-EM); ligand binding regulates synapse formation, climbing fiber connectivity, and dendritic morphogenesis, while Stabilin-2 activates BAI3's GPCR activity to recruit ELMO proteins via heterotrimeric G-proteins, coupling BAI3 to the ELMO/DOCK1/Rac1 pathway that drives both myoblast fusion and actin cytoskeleton remodeling in neurons; additionally, BAI3 mediates C1QL3-dependent inhibition of insulin secretion via cAMP signaling and regulates adaptive thermogenesis in vivo.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ADGRB3 (BAI3) is a brain-enriched adhesion G-protein-coupled receptor that transduces extracellular ligand signals into cytoskeletal remodeling, synapse organization, and metabolic regulation across multiple tissues. Its extracellular thrombospondin-repeat (TSR) and CUB domains bind C1q-like proteins (C1ql1–4) in a calcium-dependent hexameric configuration—resolved by cryo-EM—where a C1ql trimer captures three BAI3 molecules, enabling clustering at the plasma membrane to regulate synapse density, climbing fiber connectivity on cerebellar Purkinje cells, and dendritic arborization via the ELMO1/DOCK1/Rac1 pathway [PMID:21262840, PMID:40316654, PMID:41372137, PMID:25660030, PMID:23628982]. Stabilin-2 activates BAI3's GPCR signaling through heterotrimeric G-proteins, which recruit ELMO to the membrane for DOCK1/Rac1-dependent myoblast fusion, while C1ql proteins antagonize this fusogenic activity [PMID:30367035]. Beyond the nervous system, BAI3 mediates C1QL3-dependent inhibition of insulin secretion via cAMP signaling in pancreatic β-cells, participates in C1QL4-induced steroidogenesis in Leydig cells, and restrains adaptive thermogenesis in brown adipose tissue, as whole-body knockout mice exhibit increased energy expenditure and upregulated thermogenic gene expression [PMID:30228187, PMID:30608882, PMID:37367869].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Identification of C1ql1–4 as high-affinity ligands for BAI3's TSR domain established ADGRB3 as a synapse-regulating receptor with defined extracellular binding partners, answering the long-standing question of what ligands engage adhesion-GPCRs of this subfamily.\",\n      \"evidence\": \"Biochemical pulldown with purified TSR fragments and neuronal synapse density quantification in cultured neurons\",\n      \"pmids\": [\"21262840\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of C1ql–BAI3 interaction unresolved\", \"Downstream signaling pathway from C1ql binding unknown\", \"In vivo synapse phenotype not yet tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating that BAI3 drives dendritic arborization through ELMO1/Rac1 placed the receptor within a defined intracellular signaling cascade controlling neuronal morphogenesis.\",\n      \"evidence\": \"shRNA knockdown, dominant-negative overexpression in cultured neurons and Purkinje cells in vivo, Rac1 activation assay\",\n      \"pmids\": [\"23628982\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ELMO1 binding is direct or requires intermediary activation unknown\", \"Relative contribution of BAI3 versus other Rac1 activators in dendritogenesis untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showing that BAI3 directly recruits ELMO proteins to promote DOCK1/Rac1-dependent myoblast fusion extended BAI3's function beyond neurons and established it as a bona fide fusogenic receptor.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, ELMO-binding-deficient BAI3 mutants fail to rescue fusion in vivo in mouse embryos\",\n      \"pmids\": [\"24567399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of BAI3 GPCR activation during fusion unclear\", \"Identity of the extracellular cue triggering BAI3-mediated fusion in muscle unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Genetic evidence that C1QL1–BAI3 signaling specifies climbing fiber synaptic territory on Purkinje cells answered how this ligand–receptor pair functions in circuit-level synapse organization in vivo.\",\n      \"evidence\": \"Knockout/knockdown in mice with electrophysiology and immunohistochemistry quantifying climbing fiber and parallel fiber territories\",\n      \"pmids\": [\"25660030\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular signaling downstream of C1QL1–BAI3 at synapses uncharacterized\", \"Whether BAI3 GPCR activity is engaged at these synapses untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery that Stabilin-2 activates BAI3's GPCR function and that heterotrimeric G-proteins recruit ELMO to the membrane resolved how BAI3 couples GPCR signaling to cytoskeletal remodeling; C1ql proteins were shown to oppose this pathway, revealing a dual regulatory logic.\",\n      \"evidence\": \"BRET-based GPCR activation assay, proteomic/mass spectrometry interactome, BAI3 knockout mice with cardiotoxin muscle regeneration\",\n      \"pmids\": [\"30367035\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which Gα subunit mediates ELMO recruitment not identified\", \"Whether Stabilin-2 activates BAI3 in neurons unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"BAI3 was established as a functional receptor for C1QL3 in pancreatic β-cells, mediating inhibition of glucose-stimulated insulin secretion through cAMP, extending BAI3 biology to metabolic regulation.\",\n      \"evidence\": \"siRNA knockdown in INS1(832/13) cells, insulin secretion and cAMP measurement, competitive inhibition with soluble TSR fragment\",\n      \"pmids\": [\"30228187\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effectors coupling BAI3 to cAMP in β-cells unidentified\", \"In vivo validation of BAI3-dependent insulin regulation absent\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"BAI3 was implicated in C1QL4-driven steroidogenesis in Leydig cells, broadening the tissue repertoire of BAI3–C1ql signaling to endocrine function.\",\n      \"evidence\": \"siRNA knockdown in TM3 Leydig cells, StAR expression and ERK1/2/cAMP signaling analysis\",\n      \"pmids\": [\"30608882\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"An additional unidentified receptor also contributes to C1QL4 signaling\", \"In vivo relevance in steroidogenesis untested\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of a trans-synaptic complex in which C1QL3 bridges postsynaptic BAI3 to presynaptic neuronal pentraxins (NPTX1/NPTXR) revealed a higher-order adhesion architecture at synapses.\",\n      \"evidence\": \"In vivo co-immunoprecipitation, cell-cell adhesion assay, single-cell RNA-seq co-expression analysis\",\n      \"pmids\": [\"33337553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of this trans-synaptic complex on synapse strength or specificity untested\", \"Structural basis of pentameric pentraxin–trimeric C1ql interaction unknown\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Genetic epistasis placing BAI3 downstream of GluD2 in climbing fiber synaptogenesis on mature Purkinje cells clarified the signaling hierarchy controlling cerebellar synapse formation.\",\n      \"evidence\": \"BAI3 KO × GluD2 KO double-mutant mice, electrophysiology, calcium imaging, viral overexpression\",\n      \"pmids\": [\"37488606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between GluD2 and BAI3 activation unresolved\", \"Whether the epistasis reflects a shared pathway or parallel convergence unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"BAI3 knockout mice displayed reduced brain/body weight, social interaction deficits, increased energy expenditure, and enhanced adaptive thermogenesis, establishing BAI3 as a pleiotropic regulator of brain development and whole-body metabolism in vivo.\",\n      \"evidence\": \"CRISPR/Cas9 whole-body KO mice, behavioral assays, CLAMS metabolic monitoring, qRT-PCR of thermogenic genes in BAT\",\n      \"pmids\": [\"37337931\", \"37367869\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-type-specific contributions (neuronal vs. adipocyte) not dissected\", \"Molecular pathway linking BAI3 to thermogenic gene regulation unknown\", \"Both studies from a single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cryo-EM structures of C1ql1–BAI3 and C1ql3–BAI3 complexes at near-atomic resolution revealed a hexameric architecture with calcium-dependent domain-swapping in C1ql trimers capturing BAI3 CUB domains, and demonstrated that full-length C1ql1 forms linear clusters that accumulate BAI3 on the membrane to support synapse maintenance.\",\n      \"evidence\": \"Single-particle cryo-EM at 2.8 Å (C1ql3–BAI3) and complementary resolution (C1ql1–BAI3), mutagenesis of contact residues, molecular dynamics, in vivo synapse studies\",\n      \"pmids\": [\"40316654\", \"41372137\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of full-length BAI3 including 7TM domain not resolved\", \"How ligand-induced clustering triggers GPCR activation mechanistically remains unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The mechanism by which extracellular C1ql binding or Stabilin-2 engagement transmits conformational change through BAI3's GAIN/7TM domain to activate heterotrimeric G-proteins, and how this couples to distinct downstream pathways (Rac1 vs. cAMP) in different tissues, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of full-length BAI3 with 7TM domain available\", \"G-protein coupling specificity (Gα identity) not determined\", \"Tissue-specific switching between ELMO/Rac1 and cAMP pathways unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 4, 5, 8]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 4, 9, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 5, 8]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 3, 7, 11]}\n    ],\n    \"complexes\": [\n      \"C1ql–BAI3 hexameric complex\",\n      \"C1QL3–BAI3–NPTX1/NPTXR trans-synaptic complex\"\n    ],\n    \"partners\": [\n      \"C1QL1\",\n      \"C1QL3\",\n      \"C1QL4\",\n      \"ELMO1\",\n      \"DOCK1\",\n      \"STAB2\",\n      \"NPTX1\",\n      \"NPTXR\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}