Affinage

BIN3

Bridging integrator 3 · UniProt Q9NQY0

Length
253 aa
Mass
29.7 kDa
Annotated
2026-06-09
12 papers in source corpus 11 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BIN3 (MePCE/BCDIN3) is a dual-function protein that combines an RNA 5'-cap methyltransferase activity with a BAR-domain cytoskeletal adaptor role, linking transcriptional control to actin-dependent cell behavior (PMID:17363901, PMID:22740346). As a methyl-phosphate capping enzyme it methylates the γ-phosphate of the 5' guanosine of 7SK snRNA using S-adenosyl methionine, generating a cap that protects 7SK and scaffolds the repressive RNP that sequesters P-TEFb to restrain RNA Pol II elongation (PMID:22740346), and it likewise caps U6 snRNA, with a dedicated 'Bin3-Box' domain partitioning the 7SK-specific function from U6 biology (PMID:38100593). The catalytic activity itself is dispensable in vivo for 7SK binding, stabilization, and P-TEFb repression: a catalytic-dead Bin3 still stabilizes 7SK and rescues mutant phenotypes, and a separate metazoan-specific motif drives a 7SK-independent tissue function (PMID:37982586). In its second role, BIN3 acts as a BAR adaptor that binds and activates the Rho GTPases Cdc42 and Rac1 — facilitating GEF (Gef1p)-Cdc42 interaction and Cdc42 recruitment to the division site for actomyosin ring contraction and cytokinesis (PMID:17363901), regulating F-actin in lens fiber cells and myoblast migration/myofiber size (PMID:18339847, PMID:23872330), and suppressing tumor cell invasion through inhibition of a DOCK7-regulated Rho GTPase pathway downstream of EGFR signaling (PMID:35915159). The fission yeast ortholog Bmc1/Bin3 additionally serves as a stable, catalysis-independent component of the telomerase holoenzyme, promoting telomerase RNA accumulation via the LARP7-family protein Pof8 (PMID:35217638, PMID:35277511). A Drosophila role in repressing caudal mRNA translation through 7SK-dependent RNP assembly extends its developmental functions (PMID:21262214).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2001 Medium

    Established that human BIN3 is a functionally conserved BAR adaptor governing F-actin organization, by showing it could substitute for a yeast ortholog.

    Evidence Genetic complementation of S. pombe hob3Δ mutants with human BIN3 plus F-actin imaging

    PMID:11274158

    Open questions at the time
    • Did not identify the direct molecular partners through which BIN3 organizes actin
    • No mammalian-cell mechanism defined
  2. 2007 High

    Connected BIN3's actin role to a specific molecular mechanism — recruitment and activation of Cdc42 via a GEF — resolving how the BAR adaptor drives cytokinesis.

    Evidence Y2H, Co-IP, live imaging of actomyosin ring, GTP-Cdc42 pull-down, and human BIN3 complementation in S. pombe

    PMID:17363901

    Open questions at the time
    • Direct vs. GEF-bridged nature of the Cdc42 interaction in mammalian cells not resolved
    • Structural basis of the Hob3p-Gef1p-Cdc42 complex unknown
  3. 2008 Medium

    Demonstrated a physiological, tissue-selective requirement for Bin3 in F-actin maintenance and revealed an invasion-suppressor role, distinguishing its functions in normal vs. transformed cells.

    Evidence Bin3 knockout mouse, lens histology/F-actin imaging, invasion and proliferation assays in transformed cells

    PMID:18339847

    Open questions at the time
    • Molecular basis for tissue selectivity (lens fiber vs. epithelial) unexplained
    • Did not link the invasion phenotype to a defined signaling pathway
  4. 2011 High

    Revealed a wholly separate, RNA-based function: Bin3 stabilizes 7SK RNA to assemble a repressive RNP controlling caudal mRNA translation in development.

    Evidence Drosophila bin3 mutants, RNA co-IP of 7SK, Northern blot quantification, and genetic epistasis with bicoid/eIF4E/Larp1/PABP/Ago2

    PMID:21262214

    Open questions at the time
    • Did not establish whether 7SK stabilization requires catalytic methylation
    • Direct interaction map within the repressive RNP not resolved
  5. 2012 Medium

    Defined the enzymatic basis of 7SK stabilization — γ-phosphate methylation generating a protective methyl-phosphate cap that scaffolds P-TEFb sequestration.

    Evidence Review synthesizing in vitro methyltransferase assays with SAM substrate and biochemical reconstitution

    PMID:22740346

    Open questions at the time
    • Synthesizes prior biochemistry rather than presenting new primary data
    • In vivo requirement of the cap for function not tested here
  6. 2013 Medium

    Extended the Rho GTPase adaptor role to mammalian myogenesis, showing Bin3 controls both Rac1 and Cdc42 activity to drive myoblast migration and myofiber size.

    Evidence Bin3 loss-of-function in mouse myogenesis, Co-IP with Rac1/Cdc42, F-actin co-localization, GTPase assays, in vivo myofiber measurement

    PMID:23872330

    Open questions at the time
    • Whether Bin3 acts via a GEF in muscle, as in yeast, not established
    • Direct vs. indirect Rac1/Cdc42 binding not distinguished
  7. 2022 Medium

    Placed BIN3's invasion-suppressor activity in a defined signaling axis downstream of EGFR and upstream of DOCK7-Rho GTPase signaling, and showed it is pharmacologically actionable.

    Evidence Orthotopic glioblastoma models, BIN3 gain/loss, invasion and Rho GTPase pathway analysis, tofacitinib treatment

    PMID:35915159

    Open questions at the time
    • Direct molecular link between BIN3 and DOCK7 not biochemically defined
    • Relationship to BIN3's 7SK/RNA function untested
  8. 2022 High

    Uncovered a catalysis-independent scaffolding function for the ortholog Bmc1 within the telomerase holoenzyme, broadening the protein's RNP-assembly roles beyond 7SK.

    Evidence Affinity purification and Co-IP of telomerase components, methyltransferase-dead and deletion mutants, telomere length and TER1 accumulation assays in S. pombe (two independent labs)

    PMID:35217638 PMID:35277511

    Open questions at the time
    • Whether mammalian MePCE has an analogous telomerase role unknown
    • Structural basis of Bmc1-Pof8-TER1 assembly not resolved
  9. 2023 Medium

    Resolved a division of labor between BIN3's two capping activities by identifying a 'Bin3-Box' domain specifically required for 7SK, not U6, biology.

    Evidence Drosophila genetics, hybrid Amus-MePCE rescue, Bin3-Box mutagenesis, U6/7SK stability assays, human-cell MePCE loss-of-function

    PMID:38100593

    Open questions at the time
    • Mechanism by which the Bin3-Box confers 7SK specificity unknown
    • Structural definition of the domain not provided
  10. 2024 High

    Demonstrated that methyltransferase catalysis is dispensable in vivo — BIN3 stabilizes 7SK and represses P-TEFb as a non-catalytic scaffold — and identified a metazoan-specific motif driving a 7SK-independent function.

    Evidence Drosophila catalytic-dead Bin3Y795A rescue, P-TEFb genetic epistasis, Bin3ΔMSM deletion analysis, RNA binding/stabilization assays

    PMID:37982586

    Open questions at the time
    • Identity of the 7SK-independent MSM-dependent function not defined
    • How a catalytically dead enzyme retains the protective cap function mechanistically unexplained

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how BIN3's RNA-capping/RNP-scaffolding functions and its BAR-domain Rho GTPase adaptor functions are integrated within a single protein and coordinated in mammalian cells.
  • No structural model linking the methyltransferase, Bin3-Box, MSM, and BAR domains
  • Whether the two activities are spatially or temporally separated within a cell is unknown
  • Direct mammalian DOCK7 and Rho GTPase binding interfaces undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3 GO:0003723 RNA binding 2 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2 GO:0140098 catalytic activity, acting on RNA 2 GO:0016740 transferase activity 1
Localization
GO:0005856 cytoskeleton 3 GO:0005634 nucleus 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-8953854 Metabolism of RNA 2 R-HSA-1640170 Cell Cycle 1 R-HSA-1643685 Disease 1 R-HSA-74160 Gene expression (Transcription) 1
Partners
7SK RNACDC42DOCK7GEF1PPOF8RAC1
Complex memberships
7SK snRNPtelomerase holoenzyme

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Human BIN3 is a BAR adaptor protein homologous to yeast RVS161/Hob3p that regulates F-actin localization; expression of BIN3 in S. pombe hob3Δ mutants completely rescued F-actin localization defects (mislocalized patches and absent medial F-actin rings), establishing a conserved role in actin organization. Genetic complementation of S. pombe hob3Δ mutants with human BIN3; fluorescence microscopy of F-actin localization The Journal of biological chemistry Medium 11274158
2007 Hob3p (S. pombe ortholog of human BIN3) directly interacts with Cdc42p and forms a complex with the GEF Gef1p; Hob3p facilitates Gef1p-Cdc42p interaction and Cdc42p activation, recruits Cdc42p to the division site, and is required for actomyosin ring contraction and cytokinesis. Human Bin3 partially rescued GTP-Cdc42p levels and Cdc42p localization in hob3Δ cells, indicating functional conservation. Two-hybrid screening, co-immunoprecipitation, fluorescence localization, FRAP/live imaging of actomyosin ring contraction, genetic complementation with human BIN3, GTP-Cdc42p pull-down assay The EMBO journal High 17363901
2008 Homozygous deletion of Bin3 in mice causes loss of F-actin in lens fiber cells (but not epithelial cells), leading to cataract formation with vacuoles in cortical fibers; Bin3 loss also increases proliferation and invasive motility of SV40-large-T/Ras-transformed cells, while not affecting normal proliferation or F-actin organization, establishing Bin3 as a regulator of F-actin in lens and a suppressor of transformed-cell invasiveness. Bin3 knockout mouse; histology and fluorescence microscopy of lens F-actin; invasion and proliferation assays in transformed cells Cancer research Medium 18339847
2011 Drosophila Bin3 is required for repression of caudal mRNA translation; bin3 mutant embryos show elevated Caudal protein levels and head involution defects. Mechanistically, Bin3 co-immunoprecipitates with 7SK RNA; 7SK RNA is present in Bicoid complexes; Bin3 loss causes severe reduction of 7SK RNA levels and reduced Bicoid binding to the caudal 3' UTR. Genetic interactions with bicoid, eIF4E, Larp1, PABP, and Ago2 support a model where Bin3 stabilizes 7SK RNA to promote assembly of a repressive RNP on the caudal 3' UTR blocking translation initiation. Drosophila genetics (bin3 loss-of-function mutants), immunostaining for Caudal protein, RNA immunoprecipitation (co-IP of 7SK with Bin3), Northern blot for 7SK RNA levels, genetic epistasis with eIF4E/Larp1/PABP/Ago2 Developmental biology High 21262214
2012 The mammalian Bin3 ortholog MePCE (BCDIN3) methylates the γ-phosphate of the 5' guanosine of 7SK RNA using S-adenosyl methionine, generating an unusual methyl-phosphate cap that protects 7SK RNA from degradation; 7SK RNA then scaffolds an RNP complex that sequesters P-TEFb (positive transcription elongation factor b) to repress RNA Pol II elongation. Review synthesizing in vitro methyltransferase assays and biochemical reconstitution data from primary literature; enzymatic activity with SAM substrate Wiley interdisciplinary reviews. RNA Medium 22740346
2013 During myogenesis, mouse Bin3 (N-BAR domain protein) co-localizes with F-actin in lamellipodia of differentiating muscle cells and forms a complex with Rho GTPases Rac1 and Cdc42; Bin3 is a major regulator of Rac1 and Cdc42 activity in differentiated muscle cells, promoting myoblast migration and controlling myofiber size in vitro and in vivo. Bin3 loss-of-function in mouse myogenesis (siRNA/genetic); co-immunoprecipitation of Bin3 with Rac1 and Cdc42; fluorescence co-localization with F-actin; GTPase activity assays; in vivo myofiber size measurement Developmental biology Medium 23872330
2022 In EGFR-amplified glioblastoma, ligand-activated EGFR upregulates BIN3, which suppresses tumor invasion by inhibiting a DOCK7-regulated Rho GTPase pathway; this BIN3-dependent suppression of invasion can be activated therapeutically by tofacitinib (which increases EGFR ligand levels and upregulates BIN3). Orthotopic glioblastoma mouse models; BIN3 overexpression/knockdown; invasion assays; signaling pathway analysis (DOCK7, Rho GTPase activity); tofacitinib pharmacological treatment Nature cell biology Medium 35915159
2022 In S. pombe, the Bin3/MePCE ortholog Bmc1 is a stable component of the telomerase holoenzyme; Bmc1 associates with telomerase and U6 snRNA via an interaction with the LARP7-family protein Pof8, promotes TER1 (telomerase RNA) accumulation and Pof8 recruitment to TER1, and facilitates telomerase holoenzyme assembly. This association is independent of Bmc1's methyltransferase catalytic activity. Affinity purification of telomerase components; co-immunoprecipitation; genetic analysis of bmc1 mutants (methyltransferase-dead and deletion); telomere length assays; RNA accumulation assays Nature communications High 35217638 35277511
2023 Drosophila Bin3 and mammalian MePCE function as U6 snRNA capping enzymes; a 'Bin3-Box' domain present only in enzymes associated with 7SK regulation (not U6 biology) was identified by sequence analysis, and targeted mutagenesis of this domain confirmed its importance for Bin3 function in 7SK (but not U6) biology, revealing a division of labor between the two capping activities. Drosophila genetics; hybrid Amus-MePCE protein rescue experiments; targeted mutagenesis of Bin3-Box domain; RNA stability assays for U6 and 7SK snRNAs; human cell MePCE loss-of-function Science advances Medium 38100593
2024 The catalytic methyltransferase activity of Drosophila Bin3 is dispensable for 7SK snRNP function in vivo: a catalytic-dead mutant (Bin3Y795A) still binds and stabilizes 7SK RNA and rescues all bin3 mutant phenotypes (reduced egg-laying, neuromuscular defects). Furthermore, Bin3 represses P-TEFb activity in vivo (genetic reduction of P-TEFb rescues bin3 mutant phenotypes). A metazoan-specific motif (MSM) outside the methyltransferase domain is required for a 7SK-independent, tissue-specific function of Bin3. Drosophila genetics; catalytic-dead point mutant (Bin3Y795A) rescue experiments; P-TEFb genetic epistasis; Bin3ΔMSM deletion mutant analysis; RNA binding/stabilization assays Genetics High 37982586

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2022 EGFR ligand shifts the role of EGFR from oncogene to tumour suppressor in EGFR-amplified glioblastoma by suppressing invasion through BIN3 upregulation. Nature cell biology 33 35915159
2007 Hob3p, the fission yeast ortholog of human BIN3, localizes Cdc42p to the division site and regulates cytokinesis. The EMBO journal 32 17363901
2012 The Bin3 RNA methyltransferase targets 7SK RNA to control transcription and translation. Wiley interdisciplinary reviews. RNA 27 22740346
2013 The N-BAR domain protein, Bin3, regulates Rac1- and Cdc42-dependent processes in myogenesis. Developmental biology 25 23872330
2008 Bin3 deletion causes cataracts and increased susceptibility to lymphoma during aging. Cancer research 25 18339847
2001 Human BIN3 complements the F-actin localization defects caused by loss of Hob3p, the fission yeast homolog of Rvs161p. The Journal of biological chemistry 24 11274158
2011 The Bin3 RNA methyltransferase is required for repression of caudal translation in the Drosophila embryo. Developmental biology 22 21262214
2022 A putative cap binding protein and the methyl phosphate capping enzyme Bin3/MePCE function in telomerase biogenesis. Nature communications 11 35217638
2022 The methyl phosphate capping enzyme Bmc1/Bin3 is a stable component of the fission yeast telomerase holoenzyme. Nature communications 11 35277511
2023 Drosophila Amus and Bin3 methylases functionally replace mammalian MePCE for capping and the stabilization of U6 and 7SK snRNAs. Science advances 3 38100593
2024 Catalytic activity of the Bin3/MePCE methyltransferase domain is dispensable for 7SK snRNP function in Drosophila melanogaster. Genetics 2 37982586
2023 Catalytic activity of the Bin3/MEPCE methyltransferase domain is dispensable for 7SK snRNP function in Drosophila melanogaster. bioRxiv : the preprint server for biology 1 37333392

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