Affinage

ADGRB3

Adhesion G protein-coupled receptor B3 · UniProt O60242

Length
1522 aa
Mass
171.5 kDa
Annotated
2026-04-28
23 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2011 High

    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

    PMID:21262840

    Open questions at the time
    • Structural basis of C1ql–BAI3 interaction unresolved
    • Downstream signaling pathway from C1ql binding unknown
    • In vivo synapse phenotype not yet tested
  2. 2013 High

    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

    PMID:23628982

    Open questions at the time
    • Whether ELMO1 binding is direct or requires intermediary activation unknown
    • Relative contribution of BAI3 versus other Rac1 activators in dendritogenesis untested
  3. 2014 High

    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

    PMID:24567399

    Open questions at the time
    • Mechanism of BAI3 GPCR activation during fusion unclear
    • Identity of the extracellular cue triggering BAI3-mediated fusion in muscle unknown
  4. 2015 High

    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

    PMID:25660030

    Open questions at the time
    • Intracellular signaling downstream of C1QL1–BAI3 at synapses uncharacterized
    • Whether BAI3 GPCR activity is engaged at these synapses untested
  5. 2018 High

    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

    PMID:30367035

    Open questions at the time
    • Which Gα subunit mediates ELMO recruitment not identified
    • Whether Stabilin-2 activates BAI3 in neurons unknown
  6. 2018 Medium

    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

    PMID:30228187

    Open questions at the time
    • Downstream effectors coupling BAI3 to cAMP in β-cells unidentified
    • In vivo validation of BAI3-dependent insulin regulation absent
    • Single-lab finding
  7. 2019 Medium

    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

    PMID:30608882

    Open questions at the time
    • An additional unidentified receptor also contributes to C1QL4 signaling
    • In vivo relevance in steroidogenesis untested
    • Single-lab finding
  8. 2021 Medium

    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

    PMID:33337553

    Open questions at the time
    • 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
  9. 2023 High

    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

    PMID:37488606

    Open questions at the time
    • Molecular link between GluD2 and BAI3 activation unresolved
    • Whether the epistasis reflects a shared pathway or parallel convergence unclear
  10. 2023 Medium

    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

    PMID:37337931 PMID:37367869

    Open questions at the time
    • Cell-type-specific contributions (neuronal vs. adipocyte) not dissected
    • Molecular pathway linking BAI3 to thermogenic gene regulation unknown
    • Both studies from a single lab
  11. 2025 High

    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

    PMID:40316654 PMID:41372137

    Open questions at the time
    • Structure of full-length BAI3 including 7TM domain not resolved
    • How ligand-induced clustering triggers GPCR activation mechanistically remains unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098631 cell adhesion mediator activity 1
Localization
GO:0005886 plasma membrane 5
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 GO:0005886 plasma membrane 3 R-HSA-112316 Neuronal System 2
Partners
C1QL1C1QL3C1QL4DOCK1ELMO1NPTX1NPTXRSTAB2
Complex memberships
C1QL3–BAI3–NPTX1/NPTXR trans-synaptic complexC1ql–BAI3 hexameric complex

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 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. Biochemical binding assay (pulldown), neuronal synapse density quantification, competitive inhibition with TSR fragment Proceedings of the National Academy of Sciences of the United States of America High 21262840
2014 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. Co-immunoprecipitation, loss-of-function (siRNA/dominant negative), in vivo rescue experiments in mouse embryos Proceedings of the National Academy of Sciences of the United States of America High 24567399
2013 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. shRNA knockdown, overexpression, transgenic mice, lentivirus-driven knockdown, Rac1 activation assay Molecular psychiatry High 23628982
2015 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. Genetic knockdown/knockout in mice, electrophysiology, immunohistochemistry, in vivo synapse quantification Cell reports High 25660030
2018 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. Proteomic/mass spectrometry interactome, GPCR activation assay (BRET), Co-IP, BAI3 knockout mice, cardiotoxin muscle regeneration model Nature communications High 30367035
2018 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. siRNA knockdown in INS1(832/13) cells, insulin secretion assay, cAMP measurement, competitive inhibition with BAI3 fragment The Journal of biological chemistry Medium 30228187
2021 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. In vivo interactome/co-immunoprecipitation, cell-cell adhesion assay, single-cell RNA-seq co-expression analysis FASEB journal Medium 33337553
2023 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. Electrophysiology, Ca2+-imaging, immunohistochemistry, viral overexpression, genetic epistasis (BAI3 KO × GluD2 KO double mutant) Molecular brain High 37488606
2019 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. siRNA knockdown in TM3 Leydig cells, testosterone/StAR expression assay, signaling pathway analysis FASEB journal Medium 30608882
2025 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. Single-particle cryo-EM (2.8 Å), mutagenesis, cell surface staining Communications biology High 40316654
2025 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. Cryo-EM, biochemical analysis, molecular dynamics simulation, cellular and in vivo studies Nature communications High 41372137
2023 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. CRISPR/Cas9 knockout, Western blot, behavioral assays Basic & clinical pharmacology & toxicology Medium 37337931
2023 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. CRISPR/Cas9 whole-body KO, CLAMS metabolic monitoring, qRT-PCR, quantitative MRI body composition Metabolites Medium 37367869

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 The cell-adhesion G protein-coupled receptor BAI3 is a high-affinity receptor for C1q-like proteins. Proceedings of the National Academy of Sciences of the United States of America 149 21262840
2015 The Secreted Protein C1QL1 and Its Receptor BAI3 Control the Synaptic Connectivity of Excitatory Inputs Converging on Cerebellar Purkinje Cells. Cell reports 111 25660030
2014 G-protein coupled receptor BAI3 promotes myoblast fusion in vertebrates. Proceedings of the National Academy of Sciences of the United States of America 97 24567399
1997 Cloning and characterization of BAI2 and BAI3, novel genes homologous to brain-specific angiogenesis inhibitor 1 (BAI1). Cytogenetics and cell genetics 93 9533023
2013 The adhesion-GPCR BAI3, a gene linked to psychiatric disorders, regulates dendrite morphogenesis in neurons. Molecular psychiatry 75 23628982
2004 Expression of brain-specific angiogenesis inhibitor 3 (BAI3) in normal brain and implications for BAI3 in ischemia-induced brain angiogenesis and malignant glioma. FEBS letters 61 15225653
2018 Spatiotemporal regulation of the GPCR activity of BAI3 by C1qL4 and Stabilin-2 controls myoblast fusion. Nature communications 49 30367035
2013 BAI3, CDX2 and VIL1: a panel of three antibodies to distinguish small cell from large cell neuroendocrine lung carcinomas. Histopathology 42 24266897
2018 Complement 1q-like-3 protein inhibits insulin secretion from pancreatic β-cells via the cell adhesion G protein-coupled receptor BAI3. The Journal of biological chemistry 39 30228187
2021 C1QL3 promotes cell-cell adhesion by mediating complex formation between ADGRB3/BAI3 and neuronal pentraxins. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 35 33337553
2010 A multi-stage multi-design strategy provides strong evidence that the BAI3 locus is associated with early-onset venous thromboembolism. Journal of thrombosis and haemostasis : JTH 35 20946148
2019 Biallelic intragenic duplication in ADGRB3 (BAI3) gene associated with intellectual disability, cerebellar atrophy, and behavioral disorder. European journal of human genetics : EJHG 25 30659260
2021 miR-142 downregulation alleviates the impairment of spatial learning and memory, reduces the level of apoptosis, and upregulates the expression of pCaMKII and BAI3 in the hippocampus of APP/PS1 transgenic mice. Behavioural brain research 17 34302879
2023 C1ql1-Bai3 signaling is necessary for climbing fiber synapse formation in mature Purkinje cells in coordination with neuronal activity. Molecular brain 16 37488606
2021 Genetic underpinnings of affective temperaments: a pilot GWAS investigation identifies a new genome-wide significant SNP for anxious temperament in ADGRB3 gene. Translational psychiatry 16 34075027
2019 Expression patterns of C1ql4 and its cell-adhesion GPCR Bai3 in the murine testis and functional roles in steroidogenesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 16 30608882
2021 Perinatal SSRI Exposure Disrupts G Protein-coupled Receptor BAI3 in Developing Dentate Gyrus and Adult Emotional Behavior: Relevance to Psychiatric Disorders. Neuroscience 14 34293414
2022 Variants Within Genes EDIL3 and ADGRB3 are Associated With Divergent Fecal Egg Counts in Katahdin Sheep at Weaning. Frontiers in genetics 12 35360858
2023 Generation and initial characterization of mice lacking full-length BAI3 (ADGRB3) expression. Basic & clinical pharmacology & toxicology 10 37337931
2023 Loss of Brain Angiogenesis Inhibitor-3 (BAI3) G-Protein Coupled Receptor in Mice Regulates Adaptive Thermogenesis by Enhancing Energy Expenditure. Metabolites 8 37367869
2017 An investigation into the potential role of brain angiogenesis inhibitor protein 3 (BAI3) in the tumorigenesis of small-cell carcinoma: a review of the surrounding literature. Journal of receptor and signal transduction research 7 28537194
2025 Structure of the complex of C1q-like 3 protein with adhesion-GPCR BAI3. Communications biology 5 40316654
2025 Structural basis of calcium-dependent C1ql1/BAI3 assemblies in synaptic connectivity. Nature communications 1 41372137