{"gene":"BIN1","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":1996,"finding":"BIN1 physically interacts with the N-terminal Myc box regions of the MYC oncoprotein and inhibits malignant cell transformation by MYC.","method":"Genetic screen/protein interaction assay; ectopic expression growth suppression assay","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — founding paper with direct interaction assay and functional transformation suppression, replicated in multiple subsequent studies","pmids":["8782822"],"is_preprint":false},{"year":1997,"finding":"BIN1 (Amphiphysin II) localizes to the cortical cytomatrix of axon initial segments and nodes of Ranvier in brain, and concentrates around T tubules in skeletal muscle, co-localizing with ankyrin3 splice variants.","method":"Immunofluorescence, subcellular fractionation, direct localization experiments in tissue sections","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization by immunofluorescence in multiple tissue types, independently validated in subsequent studies","pmids":["9182667"],"is_preprint":false},{"year":1997,"finding":"BIN1 is a short-lived nuclear phosphoprotein (half-life ~2 h) with altered subcellular localization in tumor cells versus normal cells: predominantly nucleoplasmic in normal cells but shifted to a subnuclear compartment in tumor cells.","method":"Pulse-chase experiments, immunoprecipitation, immunofluorescence with monoclonal antibodies","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pulse-chase and immunofluorescence in multiple cell types, single lab","pmids":["9242458"],"is_preprint":false},{"year":1997,"finding":"Alternative splicing of BIN1 controls its MYC-binding capacity; one alternatively spliced exon encodes part of the MYC-binding domain, and MyoD transactivates the BIN1 promoter accounting for high muscle expression.","method":"Gene cloning, exon mapping, promoter reporter assays, cell-type-specific RT-PCR","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter reporter and splice analysis, single lab with multiple methods","pmids":["9395479"],"is_preprint":false},{"year":1998,"finding":"BIN1 promotes skeletal muscle differentiation; overexpression accelerates differentiation while antisense BIN1 impairs differentiation of C2C12 myoblasts; during differentiation BIN1 protein relocates from nucleus to cytoplasm via isoform switching.","method":"Stable antisense/sense overexpression in C2C12 cells, morphological and marker analysis of differentiation, immunolocalization","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with specific differentiation readout, single lab","pmids":["9418903"],"is_preprint":false},{"year":1999,"finding":"BIN1 interacts with and inhibits c-Myc transactivation through its Myc-binding domain (MBD), and inhibits cell proliferation via both MYC-dependent and MYC-independent mechanisms involving the BAR, U1, and SH3 domains.","method":"Co-immunoprecipitation, transcriptional reporter assays, Ras cotransformation assay, growth inhibition assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional assays (co-IP, reporter, transformation suppression), replicated across labs","pmids":["10380878"],"is_preprint":false},{"year":1999,"finding":"Aberrant inclusion of brain-specific exon 12A in BIN1 abrogates its ability to inhibit malignant transformation by c-Myc or adenovirus E1A and eliminates its ability to induce programmed cell death in melanoma cells.","method":"RT-PCR isoform analysis, ectopic expression of exon 12A-containing vs. non-containing BIN1 in transformation and apoptosis assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional comparison of isoforms in two assays, single lab","pmids":["10449755"],"is_preprint":false},{"year":2000,"finding":"BIN1 engages a caspase-independent cell death program characterized by cell shrinkage, vacuolated cytoplasm, and DNA degradation; this is abrogated by BAR domain mutation or the melanoma-associated exon 12A missplicing event, and is not blocked by Bcl-2 or caspase inhibitor ZVAD.fmk.","method":"Ectopic expression, domain mutagenesis, pharmacological inhibitors, cell death assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mechanistic dissections (domain mutants, inhibitors), single lab","pmids":["11032017"],"is_preprint":false},{"year":2001,"finding":"BIN1 mediates c-Myc-induced apoptosis in transformed primary cells via protein-protein interaction; antisense or dominant-inhibitory BIN1 reduced susceptibility to c-Myc-induced apoptosis without affecting proliferation or transformation.","method":"Antisense/dominant-negative expression, apoptosis assays in chick and rat primary transformed cells","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific apoptotic readout and protein interaction implication, single lab","pmids":["11306501"],"is_preprint":false},{"year":2003,"finding":"Constitutive knockout of murine Bin1 causes perinatal lethality with severe ventricular cardiomyopathy and disorganized myofibrils, but does not impair endocytosis, phagocytosis, actin organization, proliferation, or apoptosis in fibroblasts/macrophages.","method":"Homologous recombination knockout mouse, histology, electron microscopy, endocytosis/phagocytosis assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with specific cardiac phenotype and multiple negative controls via orthogonal assays","pmids":["12773571"],"is_preprint":false},{"year":2004,"finding":"The Exon10 (polybasic) sequence of BIN1 binds PI(4,5)P2 and also intramolecularly binds the BIN1 SH3 domain, blocking SH3-mediated binding to PxxP ligands (including dynamin); this blockage is released by PI(4,5)P2, providing a phosphoinositide-regulated SH3 domain mechanism.","method":"In vitro binding assays, PI(4,5)P2 addition/depletion experiments, cell overexpression with PI4P5-kinase, T-tubule formation assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution plus cellular functional validation, single lab with multiple orthogonal methods","pmids":["15483625"],"is_preprint":false},{"year":2005,"finding":"The BIN1 SH3 domain binds a class II SH3-binding motif in c-Myc; tumor-specific BIN1 isoforms are prevented from binding c-Myc via an intramolecular polyproline-SH3 interaction; phosphorylation of c-Myc at Ser62 inhibits BIN1 binding.","method":"NMR structure, surface plasmon resonance, biochemical binding assays, structure-based modeling","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structural data with biochemical validation of two distinct regulatory mechanisms","pmids":["15992821"],"is_preprint":false},{"year":2006,"finding":"Crystal structure of the BIN1 BAR domain at 2.0 Å resolution reveals a homodimeric crescent-shaped architecture with knobs-into-holes coiled-coil packing governing membrane-engaging concave face curvature, and identifies two potential protein-protein interaction sites on the convex face.","method":"X-ray crystallography","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at 2.0 Å with comparative structural analysis","pmids":["17059209"],"is_preprint":false},{"year":2006,"finding":"HCV NS5A protein interacts with BIN1 via NS5A's SH3-binding motif (PxxP) and BIN1's SH3 domain; this interaction inhibits BIN1-induced apoptosis and is required for productive HCV infection.","method":"Yeast two-hybrid, in vitro binding, co-immunoprecipitation, confocal microscopy, deletion/mutation analysis, HCV infectivity in chimpanzees","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and in vitro binding plus functional infectivity assay, single lab","pmids":["16530520"],"is_preprint":false},{"year":2008,"finding":"BIN1's membrane-tubulating activity depends on CLIP-170; BIN1 interacts with CLIP-170 via its BAR domain and CLIP-170's coiled-coil region; depletion of CLIP-170 reduces BIN1-induced tubule formation, and BIN1 tubules align with microtubules.","method":"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, RNAi knockdown, confocal microscopy, nocodazole depolymerization","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and pulldown with functional RNAi rescue, single lab","pmids":["19004523"],"is_preprint":false},{"year":2009,"finding":"BIN1 (AMPH-1 in C. elegans) colocalizes with RME-1/EHD1 on recycling endosomes; BIN1/AMPH-1 deletion impairs recycling endosome function; purified AMPH-1 and RME-1 together form coated membrane tubules distinct from those produced by either alone, and BIN1 is required for EHD1-regulated endocytic recycling in human cells.","method":"In vivo co-localization, deletion mutant analysis, in vitro reconstitution of membrane tubules, siRNA knockdown in human cells","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified proteins plus genetic loss-of-function in two organisms","pmids":["19915558"],"is_preprint":false},{"year":2009,"finding":"BIN1's SH3 domain acts as a scaffold for sarcomere assembly; it forms transient complexes with actin, myosin filaments, and the pro-myogenic kinase Cdk5, and associates with a Cdk5 phosphorylation domain of titin; expression of isolated SH3 domain causes myofiber disorganization.","method":"Dominant-negative expression in mouse, co-immunoprecipitation, pull-down assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple co-IP interactions with loss-of-function phenotype, single lab","pmids":["19633357"],"is_preprint":false},{"year":2009,"finding":"BIN1 is a transcriptional target of E2F1 (via canonical E2F sites in the BIN1 promoter) and mediates E2F1-induced apoptosis in response to DNA damage; BIN1 suppression attenuates E2F1/etoposide-induced cell death independently of p53, p73, and caspases.","method":"Promoter reporter assay, ChIP, siRNA knockdown, antisense suppression, DNA damage apoptosis assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional reporter and loss-of-function assays, single lab","pmids":["19629135"],"is_preprint":false},{"year":2010,"finding":"BIN1 localizes to cardiac T-tubules and clusters there with L-type calcium channel Cav1.2; dynamic microtubules tethered to BIN1-scaffolded membrane enable targeted delivery of Cav1.2; BIN1 knockdown reduces surface Cav1.2 and delays calcium transient development.","method":"Immunocytochemistry, electron microscopy with dual immunogold labeling, co-immunoprecipitation, surface biotinylation, live-cell confocal/TIRF microscopy, shRNA knockdown","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (EM-immunogold, co-IP, live imaging, biotinylation) with functional KD phenotype; replicated in follow-up studies","pmids":["20169111"],"is_preprint":false},{"year":2011,"finding":"BIN1 is required for skeletal muscle T-tubule biogenesis and excitation-contraction coupling; Bin1 knockdown in adult mouse skeletal muscle disrupts T-tubule structure, reduces DHPR-RyR1 coupling, and impairs SR Ca2+ release.","method":"In vivo electroporation shRNA delivery, confocal imaging of T-tubules, patch-clamp, Ca2+ spark and transient measurements","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo shRNA knockdown with specific electrophysiology readout, single lab","pmids":["21984944"],"is_preprint":false},{"year":2011,"finding":"BIN1 is significantly reduced (~36% protein) in failing human cardiomyocytes, and this reduction impairs Cav1.2 trafficking to T-tubules, reduces calcium transients, and causes contractile dysfunction (75% reduction in calcium transients in BIN1-knockdown zebrafish hearts).","method":"Human failing heart tissue analysis, immunostaining, biochemical fractionation, patch-clamp in cell lines, mouse cardiomyocyte shRNA knockdown, zebrafish morpholino knockdown","journal":"Heart rhythm","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple species models with electrophysiology and contractility readouts, confirms mechanistic link from earlier study","pmids":["22138472"],"is_preprint":false},{"year":2011,"finding":"MBNL1 binds the BIN1 pre-mRNA and regulates its alternative splicing; in myotonic dystrophy, BIN1 missplicing produces an inactive BIN1 form lacking PI(5)P-binding and membrane-tubulating activities, causing T-tubule alterations; reproducing this splicing alteration in mice is sufficient to cause T-tubule defects and muscle weakness.","method":"RNA binding assay (MBNL1-BIN1 pre-mRNA), functional splicing assays, rescue experiments in patient muscle cells, transgenic mouse model","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic chain from splicing factor binding to biochemical loss-of-function to in vivo mouse phenotype","pmids":["21623381"],"is_preprint":false},{"year":2011,"finding":"BIN1 binds the automodification domain of PARP1 and suppresses its catalytic activity; c-MYC represses BIN1 expression (by blocking MIZ1-mediated activation) thereby releasing PARP1 activity and increasing cisplatin resistance.","method":"Co-immunoprecipitation, PARP1 activity assay, siRNA knockdown, promoter analysis, cisplatin resistance assays","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding and enzymatic suppression demonstrated with co-IP and activity assay, mechanistic pathway established with multiple orthogonal experiments","pmids":["21447800"],"is_preprint":false},{"year":2012,"finding":"BIN1 interacts with Tau and they co-localize in human neuroblastoma cells and mouse brain; decreased expression of the Drosophila BIN1 ortholog Amph suppresses Tau-mediated neurotoxicity in three assays.","method":"Co-immunoprecipitation, co-localization confocal microscopy, Drosophila genetic suppressor assay","journal":"Molecular psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP in mammalian cells plus epistasis in Drosophila, single lab","pmids":["23399914"],"is_preprint":false},{"year":2012,"finding":"Transient structure in the intrinsically disordered c-Myc transactivation domain (residues 22-33 and MB1) mediates binding to BIN1 SH3 domain; Bin1 binds primarily to the Ser62 region of c-Myc in a dynamically disordered, multivalent complex; binding causes population shifts in Myc conformational dynamics.","method":"NMR chemical shift analysis, relaxation measurements, NOE analysis, surface plasmon resonance","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural characterization with SPR quantification, single lab with multiple orthogonal biophysical methods","pmids":["22457068"],"is_preprint":false},{"year":2013,"finding":"BIN1 directly interacts with Tau through its SH3 domain binding Tau's proline-rich domain; BIN1-Tau complexes co-localize with the actin cytoskeleton in primary neurons; phosphorylation of Tau at Thr231 weakens the SH3-PRD interaction.","method":"GST pulldown, NMR, co-localization in primary neurons, phospho-specific analysis","journal":"Acta neuropathologica communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro pulldown and NMR with cellular co-localization validation, single lab","pmids":["26395440"],"is_preprint":false},{"year":2014,"finding":"A cardiac-specific isoform of BIN1 (BIN1+13+17) promotes N-WASP-dependent actin polymerization to fold T-tubule inner membranes at Z-discs, creating a 'fuzzy space' that restricts local ion diffusion; cardiac Bin1 deletion decreases T-tubule folding, allowing free diffusion of Ca2+ and K+, prolonging action potential duration and increasing arrhythmia susceptibility.","method":"Cardiac-specific Bin1 knockout mouse, electrophysiology, superresolution microscopy, BIN1 isoform re-expression, N-WASP interaction assay","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple orthogonal readouts (electrophysiology, imaging, isoform rescue), mechanistic pathway to N-WASP actin polymerization established","pmids":["24836577"],"is_preprint":false},{"year":2014,"finding":"BIN1/M-Amphiphysin2 clusters PtdIns(4,5)P2 on membranes to recruit dynamin; the N-BAR domain controls kinetics and accumulation of dynamin while the SH3 domain controls its accumulation on membranes; CNM-associated BIN1 mutants show defects in this process.","method":"In vitro membrane binding assays, fluorescence microscopy, CNM mutant analysis, numerical simulations","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biochemical reconstitution on membranes with multiple mutant validations and numerical modeling, single lab","pmids":["25487648"],"is_preprint":false},{"year":2014,"finding":"BIN1 knockdown by siRNA reduces t-tubule density, calcium transient amplitude, and synchrony of systolic calcium transient in rat cardiac cells; AmpII protein levels correlate with t-tubule density across cardiac chambers and heart failure models.","method":"siRNA knockdown, di-4-ANEPPS/FM4-64 t-tubule staining, calcium transient measurements, Western blot across species/chamber comparisons","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with functional calcium and t-tubule readouts in multiple models, single lab","pmids":["25332206"],"is_preprint":false},{"year":2014,"finding":"BIN1 membrane curvature sensing and generation is autoinhibited by intramolecular exon10-SH3 interaction on membranes lacking PI(4,5)P2; addition of PI(4,5)P2 or SH3 domain ligands (PRD peptides) relieves autoinhibition and activates BIN1 membrane deformation.","method":"In vitro membrane deformation assays, SH3-exon10 binding assays, PI(4,5)P2 titration, CNM mutant analysis","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with multiple mutants and lipid titration, single lab","pmids":["25350771"],"is_preprint":false},{"year":2014,"finding":"CNM-associated BIN1 mutants R154Q and D151N disrupt membrane tubulation through distinct mechanisms: R154Q reduces membrane-bound protein density while D151N impairs protein oligomerization upon membrane binding.","method":"In vitro liposome tubulation assays, protein density quantification, chemical crosslinking, live-cell depolymerization assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution with mutant analysis, single lab","pmids":["24755653"],"is_preprint":false},{"year":2015,"finding":"Cryo-EM reveals that BIN1 N-BAR domains self-assemble cooperatively on membrane tubes; the N-terminal amphipathic helix H0 initiates tube assembly and organizes BAR-mediated polymerization by locking adjacent N-BAR domains; loss of H0 or BAR tip disrupts polymer organization.","method":"Cryo-EM, 3D reconstruction, biochemical tubulation assays with mutants","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structural data with biochemical mutant validation, single lab","pmids":["26487375"],"is_preprint":false},{"year":2016,"finding":"Isoproterenol (β-adrenergic activation) promotes BIN1 redistribution to T-tubules and recruits phosphorylated RyR2 (P-RyR) into BIN1+13+17-organized dyads via coimmunoprecipitation; in cardiac-specific Bin1 heterozygous mice, isoproterenol fails to concentrate BIN1 and recruit P-RyRs, resulting in uncoupled P-RyRs and spontaneous calcium release.","method":"Co-immunoprecipitation, superresolution fluorescent imaging, cardiac-specific Bin1 heterozygous mice, calcium imaging","journal":"Circulation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and superresolution imaging with genetic model, single lab","pmids":["26733606"],"is_preprint":false},{"year":2016,"finding":"EHBP1L1 directly binds GTP-loaded Rab8 and BIN1, forming a complex with dynamin at the endocytic recycling compartment; this complex is required for apical-directed vesicular transport in polarized epithelial cells.","method":"Co-immunoprecipitation, biochemical binding assays, overexpression/knockdown in organoids and cells, EHBP1L1-KO mouse","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and co-IP with functional KD phenotype, single lab","pmids":["26833786"],"is_preprint":false},{"year":2017,"finding":"BIN1 acts as a negative regulator of Dynamin 2 (DNM2) during muscle maturation; Bin1-/- Dnm2+/- double-null mice survive (unlike Bin1-/- alone) with normal muscle; BIN1 colocalized with and partially inhibited DNM2 activity in vitro during muscle maturation but not for the adult muscle DNM2 isoform.","method":"Genetic epistasis (Bin1-/- Dnm2+/- mice), in vitro DNM2 GTPase activity assay, co-localization","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis rescue experiment in vivo plus in vitro enzymatic assay, single lab with multiple orthogonal approaches","pmids":["29130937"],"is_preprint":false},{"year":2017,"finding":"Bin1 BAR domain directly binds actin filaments, has moderate actin bundling activity, stabilizes actin filaments against depolymerization, and stabilizes tau-induced actin bundles; knockdown of Bin1 in a Drosophila tauopathy model reduces tau-induced actin inclusions.","method":"In vitro actin binding/bundling assays, F-actin co-sedimentation, Drosophila genetic KD with actin inclusion quantification","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution plus in vivo Drosophila validation, single lab","pmids":["28893863"],"is_preprint":false},{"year":2018,"finding":"NMR structural model of BIN1 SH3 domain binding to Tau peptide (213-229) shows P216 and P219 contact BIN1 SH3 aromatic residues F588 and W562, while R221 and K224 of Tau form electrostatic contacts with E556/E557 of BIN1; phosphorylation of Tau at T212, T217, T231, and S235 reduces interaction with BIN1 SH3 five-fold (Kd 44 to 256 μM) and prevents Tau from competing with BIN1's intramolecular SH3-CLAP interaction.","method":"NMR spectroscopy, SPR, competition binding assays","journal":"Frontiers in molecular neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural model with quantitative binding measurements, extends prior structural work","pmids":["30487734"],"is_preprint":false},{"year":2018,"finding":"BIN1 expression in hESC-derived cardiomyocytes induces T-tubule development, promotes Cav1.2 clustering along T-tubules, increases coupled Cav1.2 gating probability, anchors sarcoplasmic reticulum, and increases Cav1.2-RyR junctions.","method":"BIN1 transfection in hESC-CMs, electrophysiology, superresolution microscopy, Ca2+ imaging","journal":"Stem cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with multiple functional readouts, single lab","pmids":["30353632"],"is_preprint":false},{"year":2019,"finding":"BIN1 interacts with Tau via SH3-PRD interaction; calcineurin dephosphorylates BIN1 at Thr348 (a CDK phosphorylation site), promoting open BIN1 conformation and increasing availability of SH3 domain for Tau binding as demonstrated by NMR; phospho-BIN1(T348):BIN1 ratio is increased in AD brains.","method":"NMR spectroscopy, high-content screening (1126 compounds), calcineurin inhibitor pharmacology, primary neuron experiments, AD brain biochemistry","journal":"Acta neuropathologica","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural validation of phosphorylation-regulated conformational change with in vivo confirmation in neurons and AD tissue, single lab","pmids":["31065832"],"is_preprint":false},{"year":2019,"finding":"BIN1 loss in microglia reduces Tau secretion via extracellular vesicles in vitro and decreases Tau spreading in vivo in male PS19 mice; microglial Bin1 deletion reduces heat-shock protein expression previously linked to Tau proteostasis.","method":"Cre-lox microglia-specific Bin1 conditional knockout, extracellular vesicle Tau quantification, in vivo tau spreading assay in PS19 mice","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with functional EV-Tau readout in vitro and in vivo, single lab, sex-specific effect","pmids":["31263146"],"is_preprint":false},{"year":2019,"finding":"BIN1 interacts with L-type voltage-gated calcium channels (LVGCCs) in rat hippocampal neurons and mouse brain; BIN1-LVGCC interactions are modulated by Tau; increasing neuronal BIN1 expression induces network hyperexcitability and increased calcium transients; Tau reduction prevents BIN1-induced hyperexcitability.","method":"Co-immunoprecipitation, multielectrode array recordings, calcium imaging, Tau reduction genetic experiments in hippocampal neurons","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with functional MEA and calcium readouts and epistasis with Tau, single lab","pmids":["32657270"],"is_preprint":false},{"year":2019,"finding":"Neuronal BIN1 loss-of-function impairs spatial learning and memory, reduces presynaptic release probability, alters synaptic vesicle dynamics (increases docked and reserve vesicle pools), reduces synapse density, and alters presynaptic active zone protein clustering; BIN1 localizes to presynaptic sites by superresolution and immunoelectron microscopy.","method":"Conditional neuronal Bin1 KO, fear conditioning/Morris water maze, electrophysiology, superresolution microscopy, immunoelectron microscopy, 3D-EM reconstruction","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with multiple orthogonal functional (electrophysiology, behavior) and structural (superresolution, EM) methods, single lab","pmids":["32160554"],"is_preprint":false},{"year":2019,"finding":"BIN1 loss-of-function in neurons does not regulate Aβ generation in vivo: 50% global BIN1 reduction or conditional neuronal BIN1 KO does not alter BACE1 levels, localization, APP processing, or Aβ deposition in the 5XFAD mouse model.","method":"Bin1 heterozygous KO mice, conditional neuronal KO, 5XFAD amyloidosis model, biochemistry, immunohistochemistry","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — negative result established by genetic reduction in vivo across multiple models, single lab; important negative mechanistic finding","pmids":["30692199"],"is_preprint":false},{"year":2019,"finding":"BIN1 loss enables ATM activation via E2F1: BIN1 inactivates ATM kinase particularly when bound to E2F1; BIN1 prevents E2F1 from transcriptionally activating the ATM promoter; BIN1 loss increases MRE11A/RAD50/NBS1 complex formation and promotes ATM autophosphorylation and γH2AX, driving cisplatin resistance.","method":"Co-immunoprecipitation, promoter reporter assays, siRNA knockdown, ATM kinase assays, cisplatin sensitivity assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple co-IP and functional assays establishing E2F1-ATM pathway, single lab","pmids":["30733337"],"is_preprint":false},{"year":2020,"finding":"BIN1 localizes to postsynaptic compartments (dendritic spines); participates in protein complexes with Arf6 and GluA1; manipulations of BIN1 alter AMPA receptor surface expression, trafficking, spine morphology, and AMPA receptor-mediated synaptic transmission.","method":"Superresolution SIM microscopy, co-immunoprecipitation, AMPA receptor surface biotinylation, electrophysiology, BIN1 knockdown/overexpression","journal":"Molecular psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of BIN1-Arf6-GluA1 complex with functional trafficking and electrophysiology readout, single lab","pmids":["30967682"],"is_preprint":false},{"year":2020,"finding":"Neuronal Bin1 conditional KO reduces neuronal excitability in vitro and alters microglial transcriptome in vivo; in PS19 Tau transgenic background, neuronal Bin1 loss increases mortality without worsening neuropathology.","method":"Conditional KO (Thy1-Cre x Bin1flox/flox x PS19), electrophysiology in primary neurons, c-fos immunostaining, microglial transcriptomics","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with electrophysiology and transcriptomics readouts, single lab","pmids":["31408457"],"is_preprint":false},{"year":2020,"finding":"Dynamin 2 GTPase activity is suppressed through interaction with BIN1; CNM disease-associated mutant dynamin 2 retains active GTPase due to lack of BIN1-mediated regulation, causing aberrant membrane fission and remodeling in T-tubule equivalent structures.","method":"In cellulo reconstitution assay, GTPase activity measurements, BIN1-DNM2 interaction assays, CNM mutant analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biochemical reconstitution with GTPase activity assay and disease mutant validation, single lab","pmids":["33187981"],"is_preprint":false},{"year":2021,"finding":"Muscle-specific Bin1 knockout (Bin1mck-/-) mice recapitulate centronuclear myopathy with T-tubule and mitochondria network defects and impaired calcium homeostasis; DNM2 antisense oligonucleotides rescue force and histology, confirming BIN1-DNM2 functional pathway in vivo.","method":"Muscle-specific conditional KO, force measurements, histology, electron microscopy, Ca2+ homeostasis, ASO treatment","journal":"Molecular therapy","confidence":"High","confidence_rationale":"Tier 2 / Strong — faithful mammalian genetic model with multiple orthogonal phenotype assays and therapeutic epistasis rescue","pmids":["34371181"],"is_preprint":false},{"year":2021,"finding":"Cavin4 directly interacts with Bin1 (Cavin4b in zebrafish) and localizes to T-tubules; loss of Cavin4 causes aberrant T-tubule maturation and accumulation of interconnected caveolae within T-tubules, impairing Ca2+ response; Cavin4 is proposed to remodel T-tubule membrane by recycling caveolar components.","method":"Direct interaction assay (Cavin4b-Bin1), Cavin4 KO mouse and zebrafish, confocal microscopy, Ca2+ imaging","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction assay with genetic KO in two organisms and functional Ca2+ readout, single lab","pmids":["34633413"],"is_preprint":false},{"year":2021,"finding":"LOAD-associated BIN1 coding variants (rs754834233, rs138047593) reduce BIN1 interaction with BACE1 and fail to rescue BACE1 recycling impaired by Bin1 knockdown; BIN1 normally promotes BACE1 recycling from early endosomes, and its loss increases intracellular Aβ42 by enabling BACE1 cleavage of APP in enlarged early endosomes.","method":"Co-immunoprecipitation of BIN1-BACE1, early endosome morphology assay, Aβ ELISA, BACE1 recycling assay, BIN1 variant overexpression/knockdown rescue","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP interaction with specific disease variants and functional endocytic recycling assay, single lab","pmids":["34375641"],"is_preprint":false},{"year":2022,"finding":"BIN1 isoform 1 (neuronal) overexpression causes early endosome accumulation and neurodegeneration in Drosophila and human induced neurons; BIN1 KO narrows early endosomes; isoform 1 rescues BIN1-KO early endosome phenotype but isoform 9 does not, identifying isoform-specific control of early endosome size.","method":"Drosophila overexpression, hiN and cerebral organoid BIN1 KO, endosome morphometry, isoform rescue experiments","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO and isoform rescue in two human cell models plus Drosophila, single lab","pmids":["34998435"],"is_preprint":false},{"year":2022,"finding":"Neuronal BIN1 isoform 1 (BIN1V1) but not isoform 9 (BIN1V9) downregulates BACE1-mediated APP processing and Aβ generation in a RIN3-dependent manner; BIN1V1 delays APP (but not BACE1) endocytosis into early endosomes, spatially separating APP from BACE1; RIN3 sequesters BIN1V1 via CLAP domain into RAB5+ endosomes.","method":"Confocal microscopy, Western blot, Aβ ELISA, surface biotinylation APP internalization assay, FACS-enriched cell populations, isoform transfection","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific functional assays with APP internalization and Aβ measurement, single lab","pmids":["35241726"],"is_preprint":false},{"year":2022,"finding":"Microglial BIN1 regulates proinflammatory and disease-associated microglial activation; BIN1 loss impairs type 1 interferon responses in microglia, particularly upregulation of Ifitm3; Bin1 regulates transcription factors PU.1 and IRF1, and loss of microglial Bin1 in vivo alters disease-associated gene expression and CX3CR1 signaling.","method":"siRNA Bin1 knockdown in primary microglia, Cre-lox microglia-specific conditional KO, NanoString transcriptomics, flow cytometry, cytokine measurement","journal":"Molecular neurodegeneration","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional microglial KO in vivo with transcriptomic and cytokine readouts, single lab with orthogonal in vitro and in vivo approaches","pmids":["35526014"],"is_preprint":false},{"year":2023,"finding":"BIN1, MTM1, and DNM2 have balanced roles in T-tubule growth in cardiomyocytes: all four cardiac BIN1 isoforms induce tubulation but with different geometries; high MTM1 (phosphoinositide phosphatase) levels are necessary for BIN1-induced tubulation (without direct binding to cardiac BIN1 isoforms lacking exon 11); high DNM2 levels are inhibitory for T-tubule formation despite DNM2 binding all four BIN1 isoforms and co-localizing at Z-lines.","method":"Developing mouse cardiomyocytes, gene-modified HL-1 and hiPSC-derived cardiomyocytes, confocal/Airyscan microscopy, RT-qPCR, Western blot, Ca2+ recording, co-IP","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple isoforms characterized with co-IP and tubulation assays, genetic and pharmacological perturbations, single lab","pmids":["37139790"],"is_preprint":false},{"year":2005,"finding":"Bin1 loss elevates STAT1- and NF-κB-dependent expression of IDO in tumor cells, promoting immune escape from T cell-dependent antitumor immunity; Bin1 knockout studies establish that Bin1 loss upregulates IDO expression.","method":"Mouse knockout studies, STAT1/NF-κB pathway analysis, IDO expression measurement, immune escape assays in MMTV-Neu mice","journal":"Nature medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO mouse with defined pathway analysis (STAT1/NF-κB-IDO), single lab","pmids":["15711557"],"is_preprint":false}],"current_model":"BIN1 (Amphiphysin II) is a multi-domain BAR adaptor protein whose crescent-shaped N-BAR domain senses and generates membrane curvature in a PI(4,5)P2-regulated, autoinhibited manner; it scaffolds T-tubule biogenesis in muscle and heart by recruiting Cav1.2 via microtubule-tethered delivery and promoting N-WASP-dependent actin polymerization, while negatively regulating Dynamin 2 GTPase activity; in the nucleus it suppresses MYC transactivation, PARP1 catalytic activity, and ATM/E2F1-driven DNA repair to maintain cisplatin sensitivity; its SH3 domain directly binds Tau's proline-rich domain in a phosphorylation-regulated manner, and in neurons it controls presynaptic vesicle dynamics, AMPA receptor trafficking, and early endosome size to modulate Aβ generation and tau spreading relevant to Alzheimer's disease."},"narrative":{"mechanistic_narrative":"BIN1 (Amphiphysin II) is a multi-domain membrane-remodeling adaptor whose N-BAR domain senses and generates membrane curvature in an autoinhibited, phosphoinositide-regulated manner [PMID:25350771, PMID:17059209]. Its membrane-deforming activity is gated by an intramolecular interaction between its polybasic exon10 region and the SH3 domain, which is relieved by PI(4,5)P2 binding or by SH3 ligands such as PxxP-containing dynamin [PMID:15483625, PMID:25350771]; cryo-EM shows the N-terminal amphipathic helix H0 nucleates cooperative N-BAR polymerization on membrane tubes [PMID:26487375]. Through PI(4,5)P2 clustering BIN1 recruits and negatively regulates dynamin 2 GTPase activity, a relationship essential for T-tubule biogenesis: BIN1 scaffolds T-tubule membranes in skeletal and cardiac muscle, recruits Cav1.2 via microtubule-tethered delivery and drives N-WASP-dependent actin folding of T-tubule membranes for excitation-contraction coupling [PMID:25487648, PMID:33187981, PMID:20169111, PMID:24836577]. Genetic loss of BIN1 causes perinatal cardiomyopathy in mice [PMID:12773571] and muscle-specific deletion recapitulates centronuclear myopathy that is rescued by lowering DNM2 [PMID:34371181, PMID:29130937], while disease-linked missplicing (myotonic dystrophy via MBNL1) and CNM coding mutations impair its membrane-tubulating activity [PMID:21623381, PMID:24755653]. In the nucleus, BIN1 binds the MYC transactivation domain through its SH3 and MYC-binding domains to suppress MYC-driven transformation and to engage apoptotic and tumor-suppressive programs [PMID:8782822, PMID:10380878, PMID:15992821, PMID:22457068]; it also binds and inhibits PARP1 and restrains E2F1/ATM-driven DNA repair to maintain cisplatin sensitivity [PMID:21447800, PMID:30733337]. In neurons BIN1 controls presynaptic vesicle dynamics, synaptic transmission and AMPA receptor trafficking [PMID:32160554, PMID:30967682], and its SH3 domain directly binds the tau proline-rich domain in a phosphorylation- and conformation-regulated manner linking it to tauopathy and Alzheimer's disease [PMID:26395440, PMID:30487734, PMID:31065832].","teleology":[{"year":1996,"claim":"Established BIN1's founding identity as a MYC-interacting tumor suppressor, defining a nuclear/oncogenic axis distinct from its later membrane roles.","evidence":"Interaction screen and growth-suppression assays against MYC-transformed cells","pmids":["8782822"],"confidence":"High","gaps":["Did not define the binding domain or structural basis","Did not connect MYC suppression to membrane biology"]},{"year":1997,"claim":"Localized BIN1 to neuronal axon initial segments/nodes and muscle T-tubules, and identified it as a short-lived nuclear phosphoprotein mislocalized in tumors, foreshadowing dual nuclear and membrane functions.","evidence":"Immunofluorescence and subcellular fractionation in brain/muscle; pulse-chase and immunostaining in normal vs tumor cells","pmids":["9182667","9242458"],"confidence":"High","gaps":["Did not establish the mechanism of T-tubule targeting","Functional consequence of tumor relocalization unresolved"]},{"year":1997,"claim":"Showed alternative splicing controls MYC-binding capacity and that MyoD drives muscle expression, introducing isoform switching as a core regulatory principle.","evidence":"Exon mapping, promoter reporter, cell-type RT-PCR","pmids":["9395479"],"confidence":"Medium","gaps":["Functional impact of each splice variant not fully tested","Single-lab promoter analysis"]},{"year":1999,"claim":"Resolved that BIN1 suppresses growth by both MYC-dependent transactivation inhibition and MYC-independent mechanisms, and that brain exon 12A inclusion abolishes tumor-suppressor and apoptotic activity, linking splicing to oncogenic escape.","evidence":"Co-IP, transcriptional reporters, transformation and apoptosis assays with isoform comparison","pmids":["10380878","10449755"],"confidence":"Medium","gaps":["MYC-independent effectors not identified","Mechanism by which exon 12A blocks function unclear at the time"]},{"year":2000,"claim":"Defined a caspase-independent, BAR-domain-dependent cell death program engaged by BIN1, distinguishing its apoptotic effect from canonical pathways.","evidence":"Domain mutagenesis and pharmacological inhibitors in cell death assays","pmids":["11032017","11306501"],"confidence":"Medium","gaps":["Molecular executioners of this death program unknown","Single-lab characterization"]},{"year":2003,"claim":"Genetic knockout revealed that BIN1's essential in vivo role is cardiac, not endocytic, redirecting the field from a presumed generic endocytosis function toward muscle membrane organization.","evidence":"Constitutive Bin1 knockout mouse with histology, EM, and endocytosis/phagocytosis assays","pmids":["12773571"],"confidence":"High","gaps":["Perinatal lethality limited adult analysis","Molecular cause of cardiomyopathy not yet defined"]},{"year":2004,"claim":"Identified the phosphoinositide-gated intramolecular exon10-SH3 mechanism, explaining how BIN1's SH3-ligand binding (including dynamin) is regulated by PI(4,5)P2.","evidence":"In vitro binding, PI(4,5)P2 titration, T-tubule formation assay","pmids":["15483625"],"confidence":"High","gaps":["Did not resolve how this couples to membrane curvature generation","Single-lab biochemistry"]},{"year":2005,"claim":"Connected BIN1 loss to tumor immune escape via STAT1/NF-kB-driven IDO upregulation, broadening its tumor-suppressor role to immune evasion.","evidence":"Knockout mouse studies with pathway analysis in MMTV-Neu model","pmids":["15711557"],"confidence":"Medium","gaps":["Direct molecular link between BIN1 and IDO transcription unresolved","Single-lab finding"]},{"year":2005,"claim":"Provided structural and biochemical definition of the BIN1 SH3-MYC interaction and showed phosphorylation of MYC Ser62 and intramolecular polyproline-SH3 binding disable it in tumor isoforms.","evidence":"NMR structure, SPR, biochemical binding","pmids":["15992821"],"confidence":"High","gaps":["In vivo relevance of Ser62 regulation not tested","Dynamics of complex incompletely described"]},{"year":2006,"claim":"Crystal and interaction structures of the BAR domain and an SH3-MYC complex provided the architectural basis for membrane curvature and protein scaffolding.","evidence":"X-ray crystallography of BAR domain; yeast two-hybrid/Co-IP and infectivity for HCV NS5A binding","pmids":["17059209","16530520"],"confidence":"High","gaps":["Convex-face protein partners not all identified","How curvature is dynamically tuned in cells unresolved"]},{"year":2009,"claim":"Linked BIN1 membrane tubulation to the cytoskeleton and endocytic recycling, showing BAR-domain binding to CLIP-170, cooperative tubulation with EHD1/RME-1, and SH3 scaffolding of sarcomere components.","evidence":"Co-IP, GST pulldown, RNAi, in vitro reconstitution with purified AMPH-1/RME-1, dominant-negative expression","pmids":["19004523","19915558","19633357"],"confidence":"High","gaps":["Hierarchy among microtubule, actin and recycling functions unclear","Tissue specificity of each interaction not resolved"]},{"year":2009,"claim":"Placed BIN1 downstream of E2F1 as a transcriptional target mediating DNA-damage apoptosis independent of p53, integrating it into stress-response signaling.","evidence":"Promoter reporter, ChIP, siRNA, DNA damage apoptosis assays","pmids":["19629135"],"confidence":"Medium","gaps":["Apoptotic effectors downstream of BIN1 unidentified","Single-lab study"]},{"year":2010,"claim":"Defined the cardiac mechanism by which BIN1 scaffolds T-tubules to deliver Cav1.2 via microtubule tethering, establishing its role in calcium handling.","evidence":"Immunogold EM, Co-IP, surface biotinylation, live-cell TIRF, shRNA knockdown","pmids":["20169111"],"confidence":"High","gaps":["Did not address skeletal muscle EC coupling","Microtubule-membrane tether composition incompletely defined"]},{"year":2011,"claim":"Extended T-tubule scaffolding to skeletal muscle EC coupling and human heart failure, and identified MBNL1-dependent missplicing as a disease mechanism, plus a PARP1/MYC axis controlling cisplatin resistance.","evidence":"In vivo shRNA electroporation with electrophysiology; failing-heart tissue with multi-species knockdown; MBNL1 RNA-binding and transgenic mouse splicing model; PARP1 activity and binding assays","pmids":["21984944","22138472","21623381","21447800"],"confidence":"High","gaps":["How missplicing produces functional loss structurally not fully defined","PARP1 nuclear and membrane roles not reconciled"]},{"year":2012,"claim":"Established direct BIN1-Tau interaction and modifier genetics, opening the neurodegeneration axis, alongside biophysical characterization of the disordered MYC-BIN1 complex.","evidence":"Co-IP, co-localization, Drosophila tau-toxicity suppression; NMR/SPR of MYC transactivation domain","pmids":["23399914","22457068"],"confidence":"Medium","gaps":["Domain and residue-level basis of Tau binding not yet defined","Directionality of BIN1 effect on tau toxicity in mammals unclear"]},{"year":2013,"claim":"Mapped the BIN1 SH3-Tau proline-rich-domain interaction and its regulation by Tau Thr231 phosphorylation, defining a phospho-switch relevant to tauopathy.","evidence":"GST pulldown, NMR, primary neuron co-localization, phospho-specific analysis","pmids":["26395440"],"confidence":"High","gaps":["Cellular consequence of disrupted SH3-PRD binding not yet measured","Link to pathological aggregation unresolved"]},{"year":2014,"claim":"Provided a comprehensive mechanistic and structural model of BIN1 membrane action: autoinhibition relieved by PI(4,5)P2, PI(4,5)P2 clustering to recruit dynamin, N-WASP-dependent T-tubule folding for electrical insulation, and CNM-mutant defects in tubulation.","evidence":"In vitro membrane deformation and dynamin recruitment assays, cardiac-specific KO with superresolution and electrophysiology, liposome tubulation of CNM mutants","pmids":["25487648","25350771","26487375","24836577","25332206","24755653"],"confidence":"High","gaps":["Coupling between autoinhibition release and dynamin regulation in vivo not fully resolved","Distinct CNM mutant mechanisms not unified"]},{"year":2016,"claim":"Tied beta-adrenergic signaling and Rab8/EHBP1L1-dependent vesicular transport to BIN1, showing dynamic recruitment of phospho-RyR2 to dyads and apical trafficking roles.","evidence":"Co-IP, superresolution imaging, Bin1 heterozygous mice; binding assays and EHBP1L1-KO mouse in epithelia","pmids":["26733606","26833786"],"confidence":"Medium","gaps":["Signaling input controlling BIN1 redistribution incompletely mapped","Generalizability of Rab8 complex beyond epithelia unclear"]},{"year":2017,"claim":"Demonstrated genetically that BIN1's key muscle function is negative regulation of DNM2, with Dnm2 reduction rescuing Bin1-null lethality, and characterized BAR-domain actin stabilization relevant to tau.","evidence":"Bin1-/- Dnm2+/- epistasis mice with in vitro GTPase assay; in vitro actin binding/bundling plus Drosophila tauopathy KD","pmids":["29130937","28893863"],"confidence":"High","gaps":["Isoform-specific DNM2 regulation not fully resolved","Role of actin stabilization in disease unclear"]},{"year":2018,"claim":"Resolved the residue-level NMR structure of the BIN1 SH3-Tau interface and quantified how multisite Tau phosphorylation weakens binding and unmasks the intramolecular SH3-CLAP interaction.","evidence":"NMR, SPR, competition binding; BIN1 expression in hESC-cardiomyocytes for T-tubule induction","pmids":["30487734","30353632"],"confidence":"High","gaps":["Physiological role of competition between Tau and CLAP unclear","In vivo consequence of phospho-weakening untested here"]},{"year":2019,"claim":"Defined neuronal and glial BIN1 functions: presynaptic vesicle dynamics and learning, calcineurin-controlled conformational gating of Tau binding, microglial control of Tau spreading, an LVGCC-Tau hyperexcitability axis, and the negative result that neuronal BIN1 does not regulate Abeta in vivo.","evidence":"Conditional neuronal/microglial KO with behavior, electrophysiology, EM, NMR conformational analysis, EV-Tau quantification, MEA recordings, and 5XFAD amyloid analysis","pmids":["31065832","31263146","32160554","32657270","30692199","30733337"],"confidence":"High","gaps":["Sex-specific microglial effects not mechanistically explained","Reconciliation of pro- and anti-pathogenic neuronal roles incomplete"]},{"year":2020,"claim":"Expanded synaptic roles to postsynaptic AMPA receptor trafficking via Arf6/GluA1 complexes and clarified excitability and tau-background mortality phenotypes of neuronal Bin1 loss.","evidence":"Superresolution SIM, Co-IP, surface biotinylation, electrophysiology, conditional KO with transcriptomics, GTPase reconstitution assay","pmids":["30967682","31408457","33187981"],"confidence":"Medium","gaps":["Direct structural basis of BIN1-Arf6-GluA1 complex undefined","Integration of pre- and postsynaptic functions unresolved"]},{"year":2021,"claim":"Validated BIN1-DNM2 as a therapeutic axis in centronuclear myopathy, identified Cavin4 as a T-tubule partner, defined endosome-based control of Abeta generation, and linked LOAD coding variants to impaired BACE1 recycling.","evidence":"Muscle-specific KO with DNM2 ASO rescue; Cavin4 KO in mouse and zebrafish; Co-IP of BIN1-BACE1 with variants and endosome/Abeta assays","pmids":["34371181","34633413","34375641"],"confidence":"High","gaps":["Cardiac vs skeletal DNM2 isoform regulation differences unresolved","Mechanistic link between endosome enlargement and Abeta incompletely defined"]},{"year":2022,"claim":"Established isoform-specific neuronal control of early endosome size and BACE1/APP spatial separation (RIN3-dependent), and defined microglial BIN1 control of interferon and disease-associated activation programs.","evidence":"Drosophila and human neuron/organoid KO with isoform rescue, endosome morphometry, APP internalization and Abeta assays; microglial conditional KO with transcriptomics and cytokine measurement","pmids":["34998435","35241726","35526014"],"confidence":"Medium","gaps":["Why isoform 1 but not isoform 9 controls endosome size mechanistically unclear","In vivo contribution of microglial interferon regulation to AD pathology unresolved"]},{"year":2023,"claim":"Resolved the balanced cardiac roles of BIN1, MTM1, and DNM2 in tuning T-tubule growth geometry, integrating phosphoinositide phosphatase and fission machinery with BIN1 isoform-specific tubulation.","evidence":"Developing cardiomyocytes, gene-modified HL-1 and hiPSC-CMs, Airyscan microscopy, Co-IP, Ca2+ recording","pmids":["37139790"],"confidence":"Medium","gaps":["Quantitative stoichiometry balancing the three regulators in vivo undefined","Cardiac vs skeletal differences in MTM1 dependence unresolved"]},{"year":null,"claim":"How BIN1's distinct compartmentalized functions—nuclear MYC/PARP1/E2F1 tumor suppression, muscle T-tubule scaffolding, and neuronal endosomal/synaptic/tau roles—are coordinately partitioned by isoform expression, phosphorylation, and conformational state across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking isoform/phospho-state to compartment-specific function","Causal contribution of BIN1 variants to Alzheimer's pathogenesis mechanism still debated across opposing neuronal/microglial datasets"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[10,29,27]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[10,18,44]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[27,46,34,22]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[35,14,16]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[12,31,26]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,18,20,27]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,4,22]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[15,49,50,51]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[14,25,35]}],"pathway":[{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[19,26,47,18]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[15,33,49,27]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[21,26,47,53]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[22,43]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[41,44,40]}],"complexes":["BIN1-DNM2 membrane fission complex","T-tubule/dyad scaffold (BIN1-Cav1.2-RyR2)","BIN1-EHD1/RME-1 recycling tubule","EHBP1L1-Rab8-BIN1-dynamin complex"],"partners":["MYC","DNM2","TAU (MAPT)","PARP1","E2F1","CLIP-170","BACE1","CAV1.2 (CACNA1C)"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00499","full_name":"Myc box-dependent-interacting protein 1","aliases":["Amphiphysin II","Amphiphysin-like protein","Box-dependent myc-interacting protein 1","Bridging integrator 1"],"length_aa":593,"mass_kda":64.7,"function":"Is a key player in the control of plasma membrane curvature, membrane shaping and membrane remodeling. Required in muscle cells for the formation of T-tubules, tubular invaginations of the plasma membrane that function in depolarization-contraction coupling (PubMed:24755653). Is a negative regulator of endocytosis (By similarity). Is also involved in the regulation of intracellular vesicles sorting, modulation of BACE1 trafficking and the control of amyloid-beta production (PubMed:27179792). In neuronal circuits, endocytosis regulation may influence the internalization of PHF-tau aggregates (By similarity). May be involved in the regulation of MYC activity and the control cell proliferation (PubMed:8782822). Has actin bundling activity and stabilizes actin filaments against depolymerization in vitro (PubMed:28893863)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O00499/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BIN1","classification":"Not Classified","n_dependent_lines":17,"n_total_lines":1208,"dependency_fraction":0.014072847682119206},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000136717","cell_line_id":"CID000510","localizations":[{"compartment":"focal_adhesions","grade":3},{"compartment":"cell_contact","grade":2},{"compartment":"cytoplasmic","grade":2},{"compartment":"membrane","grade":2}],"interactors":[{"gene":"YWHAB","stoichiometry":0.2},{"gene":"AMPH","stoichiometry":0.2},{"gene":"SMCHD1","stoichiometry":0.2},{"gene":"RIN3","stoichiometry":0.2},{"gene":"SAR1A","stoichiometry":0.2},{"gene":"YWHAZ","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000510","total_profiled":1310},"omim":[{"mim_id":"619583","title":"EH DOMAIN-BINDING PROTEIN 1-LIKE 1; EHBP1L1","url":"https://www.omim.org/entry/619583"},{"mim_id":"610223","title":"RAS AND RAB INTERACTOR 3; RIN3","url":"https://www.omim.org/entry/610223"},{"mim_id":"606396","title":"BRIDGING INTEGRATOR 3; BIN3","url":"https://www.omim.org/entry/606396"},{"mim_id":"605936","title":"BRIDGING INTEGRATOR 2; BIN2","url":"https://www.omim.org/entry/605936"},{"mim_id":"602668","title":"MYOTONIC DYSTROPHY 2; DM2","url":"https://www.omim.org/entry/602668"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":1986.0},{"tissue":"tongue","ntpm":751.1}],"url":"https://www.proteinatlas.org/search/BIN1"},"hgnc":{"alias_symbol":["SH3P9","AMPH2"],"prev_symbol":["AMPHL"]},"alphafold":{"accession":"O00499","domains":[{"cath_id":"1.20.1270.60","chopping":"20-175_210-277","consensus_level":"high","plddt":91.1652,"start":20,"end":277},{"cath_id":"2.30.30.40","chopping":"524-592","consensus_level":"high","plddt":87.6468,"start":524,"end":592}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00499","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00499-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00499-F1-predicted_aligned_error_v6.png","plddt_mean":66.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BIN1","jax_strain_url":"https://www.jax.org/strain/search?query=BIN1"},"sequence":{"accession":"O00499","fasta_url":"https://rest.uniprot.org/uniprotkb/O00499.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00499/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00499"}},"corpus_meta":[{"pmid":"15711557","id":"PMC_15711557","title":"Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy.","date":"2005","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/15711557","citation_count":891,"is_preprint":false},{"pmid":"25129075","id":"PMC_25129075","title":"Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci.","date":"2014","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/25129075","citation_count":743,"is_preprint":false},{"pmid":"8782822","id":"PMC_8782822","title":"BIN1 is a novel MYC-interacting protein with features of a tumour suppressor.","date":"1996","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8782822","citation_count":323,"is_preprint":false},{"pmid":"23399914","id":"PMC_23399914","title":"Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology.","date":"2013","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/23399914","citation_count":312,"is_preprint":false},{"pmid":"21623381","id":"PMC_21623381","title":"Misregulated alternative splicing of BIN1 is associated with T tubule alterations and muscle weakness in myotonic dystrophy.","date":"2011","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21623381","citation_count":268,"is_preprint":false},{"pmid":"25365775","id":"PMC_25365775","title":"Association of Brain DNA methylation in SORL1, ABCA7, HLA-DRB5, SLC24A4, and BIN1 with pathological diagnosis of Alzheimer disease.","date":"2015","source":"JAMA neurology","url":"https://pubmed.ncbi.nlm.nih.gov/25365775","citation_count":238,"is_preprint":false},{"pmid":"9182667","id":"PMC_9182667","title":"Amphiphysin II (SH3P9; BIN1), a member of the amphiphysin/Rvs family, is concentrated in the cortical cytomatrix of axon initial segments and nodes of ranvier in brain and around T tubules in skeletal muscle.","date":"1997","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/9182667","citation_count":226,"is_preprint":false},{"pmid":"24836577","id":"PMC_24836577","title":"Cardiac BIN1 folds T-tubule membrane, controlling ion flux and limiting arrhythmia.","date":"2014","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24836577","citation_count":202,"is_preprint":false},{"pmid":"20169111","id":"PMC_20169111","title":"BIN1 localizes the L-type calcium channel to cardiac T-tubules.","date":"2010","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/20169111","citation_count":186,"is_preprint":false},{"pmid":"19915558","id":"PMC_19915558","title":"AMPH-1/Amphiphysin/Bin1 functions with RME-1/Ehd1 in endocytic recycling.","date":"2009","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19915558","citation_count":168,"is_preprint":false},{"pmid":"10449755","id":"PMC_10449755","title":"Mechanism for elimination of a tumor suppressor: aberrant splicing of a brain-specific exon causes loss of function of Bin1 in melanoma.","date":"1999","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10449755","citation_count":162,"is_preprint":false},{"pmid":"23871436","id":"PMC_23871436","title":"Bridging integrator 1 (BIN1): form, function, and Alzheimer's disease.","date":"2013","source":"Trends in molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23871436","citation_count":151,"is_preprint":false},{"pmid":"36068586","id":"PMC_36068586","title":"Hypoxia-induced exosomal circPDK1 promotes pancreatic cancer glycolysis via c-myc activation by modulating miR-628-3p/BPTF axis and degrading BIN1.","date":"2022","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36068586","citation_count":143,"is_preprint":false},{"pmid":"31263146","id":"PMC_31263146","title":"BIN1 favors the spreading of Tau via extracellular vesicles.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31263146","citation_count":137,"is_preprint":false},{"pmid":"22138472","id":"PMC_22138472","title":"BIN1 is reduced and Cav1.2 trafficking is impaired in human failing cardiomyocytes.","date":"2011","source":"Heart rhythm","url":"https://pubmed.ncbi.nlm.nih.gov/22138472","citation_count":136,"is_preprint":false},{"pmid":"9395479","id":"PMC_9395479","title":"Structural analysis of the human BIN1 gene. Evidence for tissue-specific transcriptional regulation and alternate RNA splicing.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9395479","citation_count":130,"is_preprint":false},{"pmid":"24590001","id":"PMC_24590001","title":"Amphiphysin 2 (BIN1) in physiology and diseases.","date":"2014","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/24590001","citation_count":128,"is_preprint":false},{"pmid":"27488240","id":"PMC_27488240","title":"Predominant expression of Alzheimer's disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts.","date":"2016","source":"Molecular neurodegeneration","url":"https://pubmed.ncbi.nlm.nih.gov/27488240","citation_count":108,"is_preprint":false},{"pmid":"25332206","id":"PMC_25332206","title":"Dependence of cardiac transverse tubules on the BAR domain protein amphiphysin II (BIN-1).","date":"2014","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/25332206","citation_count":108,"is_preprint":false},{"pmid":"12773571","id":"PMC_12773571","title":"Targeted disruption of the murine Bin1/Amphiphysin II gene does not disable endocytosis but results in embryonic cardiomyopathy with aberrant myofibril formation.","date":"2003","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12773571","citation_count":106,"is_preprint":false},{"pmid":"10380878","id":"PMC_10380878","title":"Bin1 functionally interacts with Myc and inhibits cell proliferation via multiple mechanisms.","date":"1999","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/10380878","citation_count":104,"is_preprint":false},{"pmid":"11032017","id":"PMC_11032017","title":"The c-Myc-interacting adaptor protein Bin1 activates a caspase-independent cell death program.","date":"2000","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/11032017","citation_count":98,"is_preprint":false},{"pmid":"9418903","id":"PMC_9418903","title":"A role for the putative tumor suppressor Bin1 in muscle cell differentiation.","date":"1998","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9418903","citation_count":97,"is_preprint":false},{"pmid":"22778941","id":"PMC_22778941","title":"Mechanisms of Cisplatin-Induced Apoptosis and of Cisplatin Sensitivity: Potential of BIN1 to Act as a Potent Predictor of Cisplatin Sensitivity in Gastric Cancer Treatment.","date":"2012","source":"International journal of surgical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/22778941","citation_count":93,"is_preprint":false},{"pmid":"15992821","id":"PMC_15992821","title":"A structure-based model of the c-Myc/Bin1 protein interaction shows alternative splicing of Bin1 and c-Myc phosphorylation are key binding determinants.","date":"2005","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15992821","citation_count":90,"is_preprint":false},{"pmid":"22457068","id":"PMC_22457068","title":"Transient structure and dynamics in the disordered c-Myc transactivation domain affect Bin1 binding.","date":"2012","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/22457068","citation_count":90,"is_preprint":false},{"pmid":"25487648","id":"PMC_25487648","title":"BIN1/M-Amphiphysin2 induces clustering of phosphoinositides to recruit its downstream partner dynamin.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25487648","citation_count":90,"is_preprint":false},{"pmid":"35526014","id":"PMC_35526014","title":"BIN1 is a key regulator of proinflammatory and neurodegeneration-related activation in microglia.","date":"2022","source":"Molecular neurodegeneration","url":"https://pubmed.ncbi.nlm.nih.gov/35526014","citation_count":87,"is_preprint":false},{"pmid":"21447800","id":"PMC_21447800","title":"c-MYC suppresses BIN1 to release poly(ADP-ribose) polymerase 1: a mechanism by which cancer cells acquire cisplatin resistance.","date":"2011","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/21447800","citation_count":85,"is_preprint":false},{"pmid":"32160554","id":"PMC_32160554","title":"Neuronal BIN1 Regulates Presynaptic Neurotransmitter Release and Memory Consolidation.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32160554","citation_count":84,"is_preprint":false},{"pmid":"28714960","id":"PMC_28714960","title":"BIN1 reverses PD-L1-mediated immune escape by inactivating the c-MYC and EGFR/MAPK signaling pathways in non-small cell lung cancer.","date":"2017","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/28714960","citation_count":84,"is_preprint":false},{"pmid":"30992433","id":"PMC_30992433","title":"The BIN1 rs744373 SNP is associated with increased tau-PET levels and impaired memory.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30992433","citation_count":79,"is_preprint":false},{"pmid":"10738240","id":"PMC_10738240","title":"Loss of heterozygosity and tumor suppressor activity of Bin1 in prostate carcinoma.","date":"2000","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/10738240","citation_count":78,"is_preprint":false},{"pmid":"25260562","id":"PMC_25260562","title":"Adult-onset autosomal dominant centronuclear myopathy due to BIN1 mutations.","date":"2014","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/25260562","citation_count":78,"is_preprint":false},{"pmid":"10652430","id":"PMC_10652430","title":"Losses of the tumor suppressor BIN1 in breast carcinoma are frequent and reflect deficits in programmed cell death capacity.","date":"2000","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/10652430","citation_count":78,"is_preprint":false},{"pmid":"29130937","id":"PMC_29130937","title":"Amphiphysin (BIN1) negatively regulates dynamin 2 for normal muscle maturation.","date":"2017","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/29130937","citation_count":72,"is_preprint":false},{"pmid":"26733606","id":"PMC_26733606","title":"Isoproterenol Promotes Rapid Ryanodine Receptor Movement to Bridging Integrator 1 (BIN1)-Organized Dyads.","date":"2016","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/26733606","citation_count":72,"is_preprint":false},{"pmid":"26395440","id":"PMC_26395440","title":"Tau phosphorylation regulates the interaction between BIN1's SH3 domain and Tau's proline-rich domain.","date":"2015","source":"Acta neuropathologica communications","url":"https://pubmed.ncbi.nlm.nih.gov/26395440","citation_count":72,"is_preprint":false},{"pmid":"11306501","id":"PMC_11306501","title":"Bin1 mediates apoptosis by c-Myc in transformed primary cells.","date":"2001","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/11306501","citation_count":68,"is_preprint":false},{"pmid":"15483625","id":"PMC_15483625","title":"Regulation of Bin1 SH3 domain binding by phosphoinositides.","date":"2004","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/15483625","citation_count":66,"is_preprint":false},{"pmid":"17059209","id":"PMC_17059209","title":"The crystal structure of the BAR domain from human Bin1/amphiphysin II and its implications for molecular recognition.","date":"2006","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17059209","citation_count":66,"is_preprint":false},{"pmid":"17699764","id":"PMC_17699764","title":"Bin1 ablation increases susceptibility to cancer during aging, particularly lung cancer.","date":"2007","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/17699764","citation_count":62,"is_preprint":false},{"pmid":"24205320","id":"PMC_24205320","title":"BIN1 is decreased in sporadic but not familial Alzheimer's disease or in aging.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24205320","citation_count":60,"is_preprint":false},{"pmid":"32657270","id":"PMC_32657270","title":"Alzheimer's disease risk gene BIN1 induces Tau-dependent network hyperexcitability.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/32657270","citation_count":57,"is_preprint":false},{"pmid":"23754947","id":"PMC_23754947","title":"Altered splicing of the BIN1 muscle-specific exon in humans and dogs with highly progressive centronuclear myopathy.","date":"2013","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23754947","citation_count":57,"is_preprint":false},{"pmid":"16530520","id":"PMC_16530520","title":"The SH3 binding motif of HCV [corrected] NS5A protein interacts with Bin1 and is important for apoptosis and infectivity.","date":"2006","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/16530520","citation_count":55,"is_preprint":false},{"pmid":"12960121","id":"PMC_12960121","title":"Expression of a MYCN-interacting isoform of the tumor suppressor BIN1 is reduced in neuroblastomas with unfavorable biological features.","date":"2003","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/12960121","citation_count":55,"is_preprint":false},{"pmid":"26833786","id":"PMC_26833786","title":"EHBP1L1 coordinates Rab8 and Bin1 to regulate apical-directed transport in polarized epithelial cells.","date":"2016","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/26833786","citation_count":53,"is_preprint":false},{"pmid":"22300662","id":"PMC_22300662","title":"Plasma BIN1 correlates with heart failure and predicts arrhythmia in patients with arrhythmogenic right ventricular cardiomyopathy.","date":"2012","source":"Heart rhythm","url":"https://pubmed.ncbi.nlm.nih.gov/22300662","citation_count":51,"is_preprint":false},{"pmid":"31065832","id":"PMC_31065832","title":"BIN1 recovers tauopathy-induced long-term memory deficits in mice and interacts with Tau through Thr348 phosphorylation.","date":"2019","source":"Acta neuropathologica","url":"https://pubmed.ncbi.nlm.nih.gov/31065832","citation_count":50,"is_preprint":false},{"pmid":"34998435","id":"PMC_34998435","title":"The Alzheimer susceptibility gene BIN1 induces isoform-dependent neurotoxicity through early endosome defects.","date":"2022","source":"Acta neuropathologica communications","url":"https://pubmed.ncbi.nlm.nih.gov/34998435","citation_count":49,"is_preprint":false},{"pmid":"30967682","id":"PMC_30967682","title":"A novel role for the late-onset Alzheimer's disease (LOAD)-associated protein Bin1 in regulating postsynaptic trafficking and glutamatergic signaling.","date":"2019","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/30967682","citation_count":49,"is_preprint":false},{"pmid":"21984944","id":"PMC_21984944","title":"Disrupted membrane structure and intracellular Ca²⁺ signaling in adult skeletal muscle with acute knockdown of Bin1.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21984944","citation_count":49,"is_preprint":false},{"pmid":"10412034","id":"PMC_10412034","title":"Induction of apoptosis and differentiation in neuroblastoma and astrocytoma cells by the overexpression of Bin1, a novel Myc interacting protein.","date":"1999","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10412034","citation_count":47,"is_preprint":false},{"pmid":"25630570","id":"PMC_25630570","title":"Bridging Integrator 1 (BIN1) Genotype Effects on Working Memory, Hippocampal Volume, and Functional Connectivity in Young Healthy Individuals.","date":"2015","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/25630570","citation_count":47,"is_preprint":false},{"pmid":"32727516","id":"PMC_32727516","title":"BIN1 protein isoforms are differentially expressed in astrocytes, neurons, and microglia: neuronal and astrocyte BIN1 are implicated in tau pathology.","date":"2020","source":"Molecular neurodegeneration","url":"https://pubmed.ncbi.nlm.nih.gov/32727516","citation_count":45,"is_preprint":false},{"pmid":"30353632","id":"PMC_30353632","title":"BIN1 Induces the Formation of T-Tubules and Adult-Like Ca2+ Release Units in Developing Cardiomyocytes.","date":"2018","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/30353632","citation_count":45,"is_preprint":false},{"pmid":"26487375","id":"PMC_26487375","title":"Structural insights into the cooperative remodeling of membranes by amphiphysin/BIN1.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26487375","citation_count":45,"is_preprint":false},{"pmid":"9242458","id":"PMC_9242458","title":"The putative tumor suppressor BIN1 is a short-lived nuclear phosphoprotein, the localization of which is altered in malignant cells.","date":"1997","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/9242458","citation_count":44,"is_preprint":false},{"pmid":"28893863","id":"PMC_28893863","title":"Bin1 directly remodels actin dynamics through its BAR domain.","date":"2017","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/28893863","citation_count":43,"is_preprint":false},{"pmid":"21129173","id":"PMC_21129173","title":"Case report of intrafamilial variability in autosomal recessive centronuclear myopathy associated to a novel BIN1 stop mutation.","date":"2010","source":"Orphanet journal of rare diseases","url":"https://pubmed.ncbi.nlm.nih.gov/21129173","citation_count":43,"is_preprint":false},{"pmid":"24755653","id":"PMC_24755653","title":"Mutations in BIN1 associated with centronuclear myopathy disrupt membrane remodeling by affecting protein density and oligomerization.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24755653","citation_count":41,"is_preprint":false},{"pmid":"19004523","id":"PMC_19004523","title":"The membrane-tubulating potential of amphiphysin 2/BIN1 is dependent on the microtubule-binding cytoplasmic linker protein 170 (CLIP-170).","date":"2008","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19004523","citation_count":41,"is_preprint":false},{"pmid":"24582639","id":"PMC_24582639","title":"Genetic variation in BIN1 gene and Alzheimer's disease risk in Han Chinese individuals.","date":"2014","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/24582639","citation_count":40,"is_preprint":false},{"pmid":"24660791","id":"PMC_24660791","title":"The benefits of staying active in old age: physical activity counteracts the negative influence of PICALM, BIN1, and CLU risk alleles on episodic memory functioning.","date":"2014","source":"Psychology and aging","url":"https://pubmed.ncbi.nlm.nih.gov/24660791","citation_count":40,"is_preprint":false},{"pmid":"30487734","id":"PMC_30487734","title":"Structural Basis of Tau Interaction With BIN1 and Regulation by Tau Phosphorylation.","date":"2018","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/30487734","citation_count":39,"is_preprint":false},{"pmid":"26578114","id":"PMC_26578114","title":"BIN1 regulates dynamic t-tubule membrane.","date":"2015","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/26578114","citation_count":38,"is_preprint":false},{"pmid":"23570733","id":"PMC_23570733","title":"BIN1 gene rs744373 polymorphism contributes to Alzheimer's disease in East Asian population.","date":"2013","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/23570733","citation_count":38,"is_preprint":false},{"pmid":"12532338","id":"PMC_12532338","title":"Immunohistochemical analysis of Bin1/Amphiphysin II in human tissues: diverse sites of nuclear expression and losses in prostate cancer.","date":"2003","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12532338","citation_count":38,"is_preprint":false},{"pmid":"17210688","id":"PMC_17210688","title":"Bin1 ablation in mammary gland delays tissue remodeling and drives cancer progression.","date":"2007","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/17210688","citation_count":37,"is_preprint":false},{"pmid":"34371181","id":"PMC_34371181","title":"Mice with muscle-specific deletion of Bin1 recapitulate centronuclear myopathy and acute downregulation of dynamin 2 improves their phenotypes.","date":"2021","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/34371181","citation_count":35,"is_preprint":false},{"pmid":"28755476","id":"PMC_28755476","title":"Regulation of the interaction between the neuronal BIN1 isoform 1 and Tau proteins - role of the SH3 domain.","date":"2017","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/28755476","citation_count":35,"is_preprint":false},{"pmid":"19629135","id":"PMC_19629135","title":"The c-MYC-interacting proapoptotic tumor suppressor BIN1 is a transcriptional target for E2F1 in response to DNA damage.","date":"2009","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/19629135","citation_count":34,"is_preprint":false},{"pmid":"36059072","id":"PMC_36059072","title":"Loss of forebrain BIN1 attenuates hippocampal pathology and neuroinflammation in a tauopathy model.","date":"2023","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/36059072","citation_count":33,"is_preprint":false},{"pmid":"30692199","id":"PMC_30692199","title":"Reduction of the expression of the late-onset Alzheimer's disease (AD) risk-factor BIN1 does not affect amyloid pathology in an AD mouse model.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30692199","citation_count":33,"is_preprint":false},{"pmid":"19211505","id":"PMC_19211505","title":"Identification of tyrosine kinase, HCK, and tumor suppressor, BIN1, as potential mediators of AHI-1 oncogene in primary and transformed CTCL cells.","date":"2009","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/19211505","citation_count":31,"is_preprint":false},{"pmid":"28473402","id":"PMC_28473402","title":"Post-Myocardial Infarction T-tubules Form Enlarged Branched Structures With Dysregulation of Junctophilin-2 and Bridging Integrator 1 (BIN-1).","date":"2017","source":"Journal of the American Heart Association","url":"https://pubmed.ncbi.nlm.nih.gov/28473402","citation_count":31,"is_preprint":false},{"pmid":"25350771","id":"PMC_25350771","title":"BIN1 membrane curvature sensing and generation show autoinhibition regulated by downstream ligands and PI(4,5)P2.","date":"2014","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25350771","citation_count":30,"is_preprint":false},{"pmid":"25939245","id":"PMC_25939245","title":"Cardiac-specific disruption of Bin1 in mice enables a model of stress- and age-associated dilated cardiomyopathy.","date":"2015","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25939245","citation_count":30,"is_preprint":false},{"pmid":"10036185","id":"PMC_10036185","title":"The murine Bin1 gene functions early in myogenesis and defines a new region of synteny between mouse chromosome 18 and human chromosome 2.","date":"1999","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/10036185","citation_count":29,"is_preprint":false},{"pmid":"27343996","id":"PMC_27343996","title":"Structural insights into the centronuclear myopathy-associated functions of BIN1 and dynamin 2.","date":"2016","source":"Journal of structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/27343996","citation_count":28,"is_preprint":false},{"pmid":"34633413","id":"PMC_34633413","title":"Cavin4 interacts with Bin1 to promote T-tubule formation and stability in developing skeletal muscle.","date":"2021","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/34633413","citation_count":28,"is_preprint":false},{"pmid":"19633357","id":"PMC_19633357","title":"Bin1 SRC homology 3 domain acts as a scaffold for myofiber sarcomere assembly.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19633357","citation_count":28,"is_preprint":false},{"pmid":"31478261","id":"PMC_31478261","title":"SRSF1-dependent alternative splicing attenuates BIN1 expression in non-small cell lung cancer.","date":"2019","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31478261","citation_count":27,"is_preprint":false},{"pmid":"35149697","id":"PMC_35149697","title":"Long non-coding RNA SNHG10 upregulates BIN1 to suppress the tumorigenesis and epithelial-mesenchymal transition of epithelial ovarian cancer via sponging miR-200a-3p.","date":"2022","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/35149697","citation_count":27,"is_preprint":false},{"pmid":"30506549","id":"PMC_30506549","title":"Aberrant accrual of BIN1 near Alzheimer's disease amyloid deposits in transgenic models.","date":"2018","source":"Brain pathology (Zurich, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/30506549","citation_count":27,"is_preprint":false},{"pmid":"33187981","id":"PMC_33187981","title":"Mutant BIN1-Dynamin 2 complexes dysregulate membrane remodeling in the pathogenesis of centronuclear myopathy.","date":"2020","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33187981","citation_count":27,"is_preprint":false},{"pmid":"34375641","id":"PMC_34375641","title":"Alzheimer's disease BIN1 coding variants increase intracellular Aβ levels by interfering with BACE1 recycling.","date":"2021","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34375641","citation_count":27,"is_preprint":false},{"pmid":"32994313","id":"PMC_32994313","title":"Differential physiological roles for BIN1 isoforms in skeletal muscle development, function and regeneration.","date":"2020","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/32994313","citation_count":27,"is_preprint":false},{"pmid":"25578476","id":"PMC_25578476","title":"BIN1 tumor suppressor regulates Fas/Fas ligand-mediated apoptosis through c-FLIP in cutaneous T-cell lymphoma.","date":"2015","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/25578476","citation_count":27,"is_preprint":false},{"pmid":"35241726","id":"PMC_35241726","title":"The neuronal-specific isoform of BIN1 regulates β-secretase cleavage of APP and Aβ generation in a RIN3-dependent manner.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/35241726","citation_count":25,"is_preprint":false},{"pmid":"12569356","id":"PMC_12569356","title":"hob1+, the fission yeast homolog of Bin1, is dispensable for endocytosis or actin organization, but required for the response to starvation or genotoxic stress.","date":"2003","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/12569356","citation_count":25,"is_preprint":false},{"pmid":"37139790","id":"PMC_37139790","title":"BIN1, Myotubularin, and Dynamin-2 Coordinate T-Tubule Growth in Cardiomyocytes.","date":"2023","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/37139790","citation_count":24,"is_preprint":false},{"pmid":"30733337","id":"PMC_30733337","title":"Loss of the tumor suppressor BIN1 enables ATM Ser/Thr kinase activation by the nuclear protein E2F1 and renders cancer cells resistant to cisplatin.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30733337","citation_count":24,"is_preprint":false},{"pmid":"28152502","id":"PMC_28152502","title":"Methylation decreases the Bin1 tumor suppressor in ESCC and restoration by decitabine inhibits the epithelial mesenchymal transition.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28152502","citation_count":24,"is_preprint":false},{"pmid":"23803295","id":"PMC_23803295","title":"Exploring the value of plasma BIN1 as a potential biomarker for alzheimer's disease.","date":"2013","source":"Journal of Alzheimer's disease : JAD","url":"https://pubmed.ncbi.nlm.nih.gov/23803295","citation_count":24,"is_preprint":false},{"pmid":"11107117","id":"PMC_11107117","title":"BIN1 inhibits colony formation and induces apoptosis in neuroblastoma cell lines with MYCN amplification.","date":"2000","source":"Medical and pediatric oncology","url":"https://pubmed.ncbi.nlm.nih.gov/11107117","citation_count":23,"is_preprint":false},{"pmid":"17218774","id":"PMC_17218774","title":"Bin1 attenuation in breast cancer is correlated to nodal metastasis and reduced survival.","date":"2007","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/17218774","citation_count":23,"is_preprint":false},{"pmid":"25022885","id":"PMC_25022885","title":"Genetic evidence for the involvement of variants at APOE, BIN1, CR1, and PICALM loci in risk of late-onset Alzheimer's disease and evaluation for interactions with APOE genotypes.","date":"2014","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/25022885","citation_count":23,"is_preprint":false},{"pmid":"31408457","id":"PMC_31408457","title":"Cell-autonomous and non-cell autonomous effects of neuronal BIN1 loss in vivo.","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/31408457","citation_count":21,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52261,"output_tokens":12410,"usd":0.171466,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":23823,"output_tokens":7742,"usd":0.156333,"stage2_stop_reason":"end_turn"},"total_usd":0.327799,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"BIN1 physically interacts with the N-terminal Myc box regions of the MYC oncoprotein and inhibits malignant cell transformation by MYC.\",\n      \"method\": \"Genetic screen/protein interaction assay; ectopic expression growth suppression assay\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — founding paper with direct interaction assay and functional transformation suppression, replicated in multiple subsequent studies\",\n      \"pmids\": [\"8782822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"BIN1 (Amphiphysin II) localizes to the cortical cytomatrix of axon initial segments and nodes of Ranvier in brain, and concentrates around T tubules in skeletal muscle, co-localizing with ankyrin3 splice variants.\",\n      \"method\": \"Immunofluorescence, subcellular fractionation, direct localization experiments in tissue sections\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization by immunofluorescence in multiple tissue types, independently validated in subsequent studies\",\n      \"pmids\": [\"9182667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"BIN1 is a short-lived nuclear phosphoprotein (half-life ~2 h) with altered subcellular localization in tumor cells versus normal cells: predominantly nucleoplasmic in normal cells but shifted to a subnuclear compartment in tumor cells.\",\n      \"method\": \"Pulse-chase experiments, immunoprecipitation, immunofluorescence with monoclonal antibodies\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pulse-chase and immunofluorescence in multiple cell types, single lab\",\n      \"pmids\": [\"9242458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Alternative splicing of BIN1 controls its MYC-binding capacity; one alternatively spliced exon encodes part of the MYC-binding domain, and MyoD transactivates the BIN1 promoter accounting for high muscle expression.\",\n      \"method\": \"Gene cloning, exon mapping, promoter reporter assays, cell-type-specific RT-PCR\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter reporter and splice analysis, single lab with multiple methods\",\n      \"pmids\": [\"9395479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"BIN1 promotes skeletal muscle differentiation; overexpression accelerates differentiation while antisense BIN1 impairs differentiation of C2C12 myoblasts; during differentiation BIN1 protein relocates from nucleus to cytoplasm via isoform switching.\",\n      \"method\": \"Stable antisense/sense overexpression in C2C12 cells, morphological and marker analysis of differentiation, immunolocalization\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with specific differentiation readout, single lab\",\n      \"pmids\": [\"9418903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"BIN1 interacts with and inhibits c-Myc transactivation through its Myc-binding domain (MBD), and inhibits cell proliferation via both MYC-dependent and MYC-independent mechanisms involving the BAR, U1, and SH3 domains.\",\n      \"method\": \"Co-immunoprecipitation, transcriptional reporter assays, Ras cotransformation assay, growth inhibition assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional assays (co-IP, reporter, transformation suppression), replicated across labs\",\n      \"pmids\": [\"10380878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Aberrant inclusion of brain-specific exon 12A in BIN1 abrogates its ability to inhibit malignant transformation by c-Myc or adenovirus E1A and eliminates its ability to induce programmed cell death in melanoma cells.\",\n      \"method\": \"RT-PCR isoform analysis, ectopic expression of exon 12A-containing vs. non-containing BIN1 in transformation and apoptosis assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional comparison of isoforms in two assays, single lab\",\n      \"pmids\": [\"10449755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"BIN1 engages a caspase-independent cell death program characterized by cell shrinkage, vacuolated cytoplasm, and DNA degradation; this is abrogated by BAR domain mutation or the melanoma-associated exon 12A missplicing event, and is not blocked by Bcl-2 or caspase inhibitor ZVAD.fmk.\",\n      \"method\": \"Ectopic expression, domain mutagenesis, pharmacological inhibitors, cell death assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mechanistic dissections (domain mutants, inhibitors), single lab\",\n      \"pmids\": [\"11032017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"BIN1 mediates c-Myc-induced apoptosis in transformed primary cells via protein-protein interaction; antisense or dominant-inhibitory BIN1 reduced susceptibility to c-Myc-induced apoptosis without affecting proliferation or transformation.\",\n      \"method\": \"Antisense/dominant-negative expression, apoptosis assays in chick and rat primary transformed cells\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific apoptotic readout and protein interaction implication, single lab\",\n      \"pmids\": [\"11306501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Constitutive knockout of murine Bin1 causes perinatal lethality with severe ventricular cardiomyopathy and disorganized myofibrils, but does not impair endocytosis, phagocytosis, actin organization, proliferation, or apoptosis in fibroblasts/macrophages.\",\n      \"method\": \"Homologous recombination knockout mouse, histology, electron microscopy, endocytosis/phagocytosis assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with specific cardiac phenotype and multiple negative controls via orthogonal assays\",\n      \"pmids\": [\"12773571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The Exon10 (polybasic) sequence of BIN1 binds PI(4,5)P2 and also intramolecularly binds the BIN1 SH3 domain, blocking SH3-mediated binding to PxxP ligands (including dynamin); this blockage is released by PI(4,5)P2, providing a phosphoinositide-regulated SH3 domain mechanism.\",\n      \"method\": \"In vitro binding assays, PI(4,5)P2 addition/depletion experiments, cell overexpression with PI4P5-kinase, T-tubule formation assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution plus cellular functional validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"15483625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The BIN1 SH3 domain binds a class II SH3-binding motif in c-Myc; tumor-specific BIN1 isoforms are prevented from binding c-Myc via an intramolecular polyproline-SH3 interaction; phosphorylation of c-Myc at Ser62 inhibits BIN1 binding.\",\n      \"method\": \"NMR structure, surface plasmon resonance, biochemical binding assays, structure-based modeling\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structural data with biochemical validation of two distinct regulatory mechanisms\",\n      \"pmids\": [\"15992821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Crystal structure of the BIN1 BAR domain at 2.0 Å resolution reveals a homodimeric crescent-shaped architecture with knobs-into-holes coiled-coil packing governing membrane-engaging concave face curvature, and identifies two potential protein-protein interaction sites on the convex face.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at 2.0 Å with comparative structural analysis\",\n      \"pmids\": [\"17059209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"HCV NS5A protein interacts with BIN1 via NS5A's SH3-binding motif (PxxP) and BIN1's SH3 domain; this interaction inhibits BIN1-induced apoptosis and is required for productive HCV infection.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding, co-immunoprecipitation, confocal microscopy, deletion/mutation analysis, HCV infectivity in chimpanzees\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and in vitro binding plus functional infectivity assay, single lab\",\n      \"pmids\": [\"16530520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"BIN1's membrane-tubulating activity depends on CLIP-170; BIN1 interacts with CLIP-170 via its BAR domain and CLIP-170's coiled-coil region; depletion of CLIP-170 reduces BIN1-induced tubule formation, and BIN1 tubules align with microtubules.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, RNAi knockdown, confocal microscopy, nocodazole depolymerization\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and pulldown with functional RNAi rescue, single lab\",\n      \"pmids\": [\"19004523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"BIN1 (AMPH-1 in C. elegans) colocalizes with RME-1/EHD1 on recycling endosomes; BIN1/AMPH-1 deletion impairs recycling endosome function; purified AMPH-1 and RME-1 together form coated membrane tubules distinct from those produced by either alone, and BIN1 is required for EHD1-regulated endocytic recycling in human cells.\",\n      \"method\": \"In vivo co-localization, deletion mutant analysis, in vitro reconstitution of membrane tubules, siRNA knockdown in human cells\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified proteins plus genetic loss-of-function in two organisms\",\n      \"pmids\": [\"19915558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"BIN1's SH3 domain acts as a scaffold for sarcomere assembly; it forms transient complexes with actin, myosin filaments, and the pro-myogenic kinase Cdk5, and associates with a Cdk5 phosphorylation domain of titin; expression of isolated SH3 domain causes myofiber disorganization.\",\n      \"method\": \"Dominant-negative expression in mouse, co-immunoprecipitation, pull-down assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple co-IP interactions with loss-of-function phenotype, single lab\",\n      \"pmids\": [\"19633357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"BIN1 is a transcriptional target of E2F1 (via canonical E2F sites in the BIN1 promoter) and mediates E2F1-induced apoptosis in response to DNA damage; BIN1 suppression attenuates E2F1/etoposide-induced cell death independently of p53, p73, and caspases.\",\n      \"method\": \"Promoter reporter assay, ChIP, siRNA knockdown, antisense suppression, DNA damage apoptosis assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional reporter and loss-of-function assays, single lab\",\n      \"pmids\": [\"19629135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"BIN1 localizes to cardiac T-tubules and clusters there with L-type calcium channel Cav1.2; dynamic microtubules tethered to BIN1-scaffolded membrane enable targeted delivery of Cav1.2; BIN1 knockdown reduces surface Cav1.2 and delays calcium transient development.\",\n      \"method\": \"Immunocytochemistry, electron microscopy with dual immunogold labeling, co-immunoprecipitation, surface biotinylation, live-cell confocal/TIRF microscopy, shRNA knockdown\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (EM-immunogold, co-IP, live imaging, biotinylation) with functional KD phenotype; replicated in follow-up studies\",\n      \"pmids\": [\"20169111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BIN1 is required for skeletal muscle T-tubule biogenesis and excitation-contraction coupling; Bin1 knockdown in adult mouse skeletal muscle disrupts T-tubule structure, reduces DHPR-RyR1 coupling, and impairs SR Ca2+ release.\",\n      \"method\": \"In vivo electroporation shRNA delivery, confocal imaging of T-tubules, patch-clamp, Ca2+ spark and transient measurements\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo shRNA knockdown with specific electrophysiology readout, single lab\",\n      \"pmids\": [\"21984944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BIN1 is significantly reduced (~36% protein) in failing human cardiomyocytes, and this reduction impairs Cav1.2 trafficking to T-tubules, reduces calcium transients, and causes contractile dysfunction (75% reduction in calcium transients in BIN1-knockdown zebrafish hearts).\",\n      \"method\": \"Human failing heart tissue analysis, immunostaining, biochemical fractionation, patch-clamp in cell lines, mouse cardiomyocyte shRNA knockdown, zebrafish morpholino knockdown\",\n      \"journal\": \"Heart rhythm\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple species models with electrophysiology and contractility readouts, confirms mechanistic link from earlier study\",\n      \"pmids\": [\"22138472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MBNL1 binds the BIN1 pre-mRNA and regulates its alternative splicing; in myotonic dystrophy, BIN1 missplicing produces an inactive BIN1 form lacking PI(5)P-binding and membrane-tubulating activities, causing T-tubule alterations; reproducing this splicing alteration in mice is sufficient to cause T-tubule defects and muscle weakness.\",\n      \"method\": \"RNA binding assay (MBNL1-BIN1 pre-mRNA), functional splicing assays, rescue experiments in patient muscle cells, transgenic mouse model\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic chain from splicing factor binding to biochemical loss-of-function to in vivo mouse phenotype\",\n      \"pmids\": [\"21623381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BIN1 binds the automodification domain of PARP1 and suppresses its catalytic activity; c-MYC represses BIN1 expression (by blocking MIZ1-mediated activation) thereby releasing PARP1 activity and increasing cisplatin resistance.\",\n      \"method\": \"Co-immunoprecipitation, PARP1 activity assay, siRNA knockdown, promoter analysis, cisplatin resistance assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding and enzymatic suppression demonstrated with co-IP and activity assay, mechanistic pathway established with multiple orthogonal experiments\",\n      \"pmids\": [\"21447800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"BIN1 interacts with Tau and they co-localize in human neuroblastoma cells and mouse brain; decreased expression of the Drosophila BIN1 ortholog Amph suppresses Tau-mediated neurotoxicity in three assays.\",\n      \"method\": \"Co-immunoprecipitation, co-localization confocal microscopy, Drosophila genetic suppressor assay\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP in mammalian cells plus epistasis in Drosophila, single lab\",\n      \"pmids\": [\"23399914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Transient structure in the intrinsically disordered c-Myc transactivation domain (residues 22-33 and MB1) mediates binding to BIN1 SH3 domain; Bin1 binds primarily to the Ser62 region of c-Myc in a dynamically disordered, multivalent complex; binding causes population shifts in Myc conformational dynamics.\",\n      \"method\": \"NMR chemical shift analysis, relaxation measurements, NOE analysis, surface plasmon resonance\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural characterization with SPR quantification, single lab with multiple orthogonal biophysical methods\",\n      \"pmids\": [\"22457068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BIN1 directly interacts with Tau through its SH3 domain binding Tau's proline-rich domain; BIN1-Tau complexes co-localize with the actin cytoskeleton in primary neurons; phosphorylation of Tau at Thr231 weakens the SH3-PRD interaction.\",\n      \"method\": \"GST pulldown, NMR, co-localization in primary neurons, phospho-specific analysis\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro pulldown and NMR with cellular co-localization validation, single lab\",\n      \"pmids\": [\"26395440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A cardiac-specific isoform of BIN1 (BIN1+13+17) promotes N-WASP-dependent actin polymerization to fold T-tubule inner membranes at Z-discs, creating a 'fuzzy space' that restricts local ion diffusion; cardiac Bin1 deletion decreases T-tubule folding, allowing free diffusion of Ca2+ and K+, prolonging action potential duration and increasing arrhythmia susceptibility.\",\n      \"method\": \"Cardiac-specific Bin1 knockout mouse, electrophysiology, superresolution microscopy, BIN1 isoform re-expression, N-WASP interaction assay\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple orthogonal readouts (electrophysiology, imaging, isoform rescue), mechanistic pathway to N-WASP actin polymerization established\",\n      \"pmids\": [\"24836577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BIN1/M-Amphiphysin2 clusters PtdIns(4,5)P2 on membranes to recruit dynamin; the N-BAR domain controls kinetics and accumulation of dynamin while the SH3 domain controls its accumulation on membranes; CNM-associated BIN1 mutants show defects in this process.\",\n      \"method\": \"In vitro membrane binding assays, fluorescence microscopy, CNM mutant analysis, numerical simulations\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical reconstitution on membranes with multiple mutant validations and numerical modeling, single lab\",\n      \"pmids\": [\"25487648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BIN1 knockdown by siRNA reduces t-tubule density, calcium transient amplitude, and synchrony of systolic calcium transient in rat cardiac cells; AmpII protein levels correlate with t-tubule density across cardiac chambers and heart failure models.\",\n      \"method\": \"siRNA knockdown, di-4-ANEPPS/FM4-64 t-tubule staining, calcium transient measurements, Western blot across species/chamber comparisons\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with functional calcium and t-tubule readouts in multiple models, single lab\",\n      \"pmids\": [\"25332206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BIN1 membrane curvature sensing and generation is autoinhibited by intramolecular exon10-SH3 interaction on membranes lacking PI(4,5)P2; addition of PI(4,5)P2 or SH3 domain ligands (PRD peptides) relieves autoinhibition and activates BIN1 membrane deformation.\",\n      \"method\": \"In vitro membrane deformation assays, SH3-exon10 binding assays, PI(4,5)P2 titration, CNM mutant analysis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with multiple mutants and lipid titration, single lab\",\n      \"pmids\": [\"25350771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CNM-associated BIN1 mutants R154Q and D151N disrupt membrane tubulation through distinct mechanisms: R154Q reduces membrane-bound protein density while D151N impairs protein oligomerization upon membrane binding.\",\n      \"method\": \"In vitro liposome tubulation assays, protein density quantification, chemical crosslinking, live-cell depolymerization assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution with mutant analysis, single lab\",\n      \"pmids\": [\"24755653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Cryo-EM reveals that BIN1 N-BAR domains self-assemble cooperatively on membrane tubes; the N-terminal amphipathic helix H0 initiates tube assembly and organizes BAR-mediated polymerization by locking adjacent N-BAR domains; loss of H0 or BAR tip disrupts polymer organization.\",\n      \"method\": \"Cryo-EM, 3D reconstruction, biochemical tubulation assays with mutants\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structural data with biochemical mutant validation, single lab\",\n      \"pmids\": [\"26487375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Isoproterenol (β-adrenergic activation) promotes BIN1 redistribution to T-tubules and recruits phosphorylated RyR2 (P-RyR) into BIN1+13+17-organized dyads via coimmunoprecipitation; in cardiac-specific Bin1 heterozygous mice, isoproterenol fails to concentrate BIN1 and recruit P-RyRs, resulting in uncoupled P-RyRs and spontaneous calcium release.\",\n      \"method\": \"Co-immunoprecipitation, superresolution fluorescent imaging, cardiac-specific Bin1 heterozygous mice, calcium imaging\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and superresolution imaging with genetic model, single lab\",\n      \"pmids\": [\"26733606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EHBP1L1 directly binds GTP-loaded Rab8 and BIN1, forming a complex with dynamin at the endocytic recycling compartment; this complex is required for apical-directed vesicular transport in polarized epithelial cells.\",\n      \"method\": \"Co-immunoprecipitation, biochemical binding assays, overexpression/knockdown in organoids and cells, EHBP1L1-KO mouse\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and co-IP with functional KD phenotype, single lab\",\n      \"pmids\": [\"26833786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BIN1 acts as a negative regulator of Dynamin 2 (DNM2) during muscle maturation; Bin1-/- Dnm2+/- double-null mice survive (unlike Bin1-/- alone) with normal muscle; BIN1 colocalized with and partially inhibited DNM2 activity in vitro during muscle maturation but not for the adult muscle DNM2 isoform.\",\n      \"method\": \"Genetic epistasis (Bin1-/- Dnm2+/- mice), in vitro DNM2 GTPase activity assay, co-localization\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis rescue experiment in vivo plus in vitro enzymatic assay, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"29130937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Bin1 BAR domain directly binds actin filaments, has moderate actin bundling activity, stabilizes actin filaments against depolymerization, and stabilizes tau-induced actin bundles; knockdown of Bin1 in a Drosophila tauopathy model reduces tau-induced actin inclusions.\",\n      \"method\": \"In vitro actin binding/bundling assays, F-actin co-sedimentation, Drosophila genetic KD with actin inclusion quantification\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution plus in vivo Drosophila validation, single lab\",\n      \"pmids\": [\"28893863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NMR structural model of BIN1 SH3 domain binding to Tau peptide (213-229) shows P216 and P219 contact BIN1 SH3 aromatic residues F588 and W562, while R221 and K224 of Tau form electrostatic contacts with E556/E557 of BIN1; phosphorylation of Tau at T212, T217, T231, and S235 reduces interaction with BIN1 SH3 five-fold (Kd 44 to 256 μM) and prevents Tau from competing with BIN1's intramolecular SH3-CLAP interaction.\",\n      \"method\": \"NMR spectroscopy, SPR, competition binding assays\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural model with quantitative binding measurements, extends prior structural work\",\n      \"pmids\": [\"30487734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BIN1 expression in hESC-derived cardiomyocytes induces T-tubule development, promotes Cav1.2 clustering along T-tubules, increases coupled Cav1.2 gating probability, anchors sarcoplasmic reticulum, and increases Cav1.2-RyR junctions.\",\n      \"method\": \"BIN1 transfection in hESC-CMs, electrophysiology, superresolution microscopy, Ca2+ imaging\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with multiple functional readouts, single lab\",\n      \"pmids\": [\"30353632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BIN1 interacts with Tau via SH3-PRD interaction; calcineurin dephosphorylates BIN1 at Thr348 (a CDK phosphorylation site), promoting open BIN1 conformation and increasing availability of SH3 domain for Tau binding as demonstrated by NMR; phospho-BIN1(T348):BIN1 ratio is increased in AD brains.\",\n      \"method\": \"NMR spectroscopy, high-content screening (1126 compounds), calcineurin inhibitor pharmacology, primary neuron experiments, AD brain biochemistry\",\n      \"journal\": \"Acta neuropathologica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural validation of phosphorylation-regulated conformational change with in vivo confirmation in neurons and AD tissue, single lab\",\n      \"pmids\": [\"31065832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BIN1 loss in microglia reduces Tau secretion via extracellular vesicles in vitro and decreases Tau spreading in vivo in male PS19 mice; microglial Bin1 deletion reduces heat-shock protein expression previously linked to Tau proteostasis.\",\n      \"method\": \"Cre-lox microglia-specific Bin1 conditional knockout, extracellular vesicle Tau quantification, in vivo tau spreading assay in PS19 mice\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with functional EV-Tau readout in vitro and in vivo, single lab, sex-specific effect\",\n      \"pmids\": [\"31263146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BIN1 interacts with L-type voltage-gated calcium channels (LVGCCs) in rat hippocampal neurons and mouse brain; BIN1-LVGCC interactions are modulated by Tau; increasing neuronal BIN1 expression induces network hyperexcitability and increased calcium transients; Tau reduction prevents BIN1-induced hyperexcitability.\",\n      \"method\": \"Co-immunoprecipitation, multielectrode array recordings, calcium imaging, Tau reduction genetic experiments in hippocampal neurons\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with functional MEA and calcium readouts and epistasis with Tau, single lab\",\n      \"pmids\": [\"32657270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Neuronal BIN1 loss-of-function impairs spatial learning and memory, reduces presynaptic release probability, alters synaptic vesicle dynamics (increases docked and reserve vesicle pools), reduces synapse density, and alters presynaptic active zone protein clustering; BIN1 localizes to presynaptic sites by superresolution and immunoelectron microscopy.\",\n      \"method\": \"Conditional neuronal Bin1 KO, fear conditioning/Morris water maze, electrophysiology, superresolution microscopy, immunoelectron microscopy, 3D-EM reconstruction\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with multiple orthogonal functional (electrophysiology, behavior) and structural (superresolution, EM) methods, single lab\",\n      \"pmids\": [\"32160554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BIN1 loss-of-function in neurons does not regulate Aβ generation in vivo: 50% global BIN1 reduction or conditional neuronal BIN1 KO does not alter BACE1 levels, localization, APP processing, or Aβ deposition in the 5XFAD mouse model.\",\n      \"method\": \"Bin1 heterozygous KO mice, conditional neuronal KO, 5XFAD amyloidosis model, biochemistry, immunohistochemistry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — negative result established by genetic reduction in vivo across multiple models, single lab; important negative mechanistic finding\",\n      \"pmids\": [\"30692199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BIN1 loss enables ATM activation via E2F1: BIN1 inactivates ATM kinase particularly when bound to E2F1; BIN1 prevents E2F1 from transcriptionally activating the ATM promoter; BIN1 loss increases MRE11A/RAD50/NBS1 complex formation and promotes ATM autophosphorylation and γH2AX, driving cisplatin resistance.\",\n      \"method\": \"Co-immunoprecipitation, promoter reporter assays, siRNA knockdown, ATM kinase assays, cisplatin sensitivity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple co-IP and functional assays establishing E2F1-ATM pathway, single lab\",\n      \"pmids\": [\"30733337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BIN1 localizes to postsynaptic compartments (dendritic spines); participates in protein complexes with Arf6 and GluA1; manipulations of BIN1 alter AMPA receptor surface expression, trafficking, spine morphology, and AMPA receptor-mediated synaptic transmission.\",\n      \"method\": \"Superresolution SIM microscopy, co-immunoprecipitation, AMPA receptor surface biotinylation, electrophysiology, BIN1 knockdown/overexpression\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of BIN1-Arf6-GluA1 complex with functional trafficking and electrophysiology readout, single lab\",\n      \"pmids\": [\"30967682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Neuronal Bin1 conditional KO reduces neuronal excitability in vitro and alters microglial transcriptome in vivo; in PS19 Tau transgenic background, neuronal Bin1 loss increases mortality without worsening neuropathology.\",\n      \"method\": \"Conditional KO (Thy1-Cre x Bin1flox/flox x PS19), electrophysiology in primary neurons, c-fos immunostaining, microglial transcriptomics\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with electrophysiology and transcriptomics readouts, single lab\",\n      \"pmids\": [\"31408457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Dynamin 2 GTPase activity is suppressed through interaction with BIN1; CNM disease-associated mutant dynamin 2 retains active GTPase due to lack of BIN1-mediated regulation, causing aberrant membrane fission and remodeling in T-tubule equivalent structures.\",\n      \"method\": \"In cellulo reconstitution assay, GTPase activity measurements, BIN1-DNM2 interaction assays, CNM mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical reconstitution with GTPase activity assay and disease mutant validation, single lab\",\n      \"pmids\": [\"33187981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Muscle-specific Bin1 knockout (Bin1mck-/-) mice recapitulate centronuclear myopathy with T-tubule and mitochondria network defects and impaired calcium homeostasis; DNM2 antisense oligonucleotides rescue force and histology, confirming BIN1-DNM2 functional pathway in vivo.\",\n      \"method\": \"Muscle-specific conditional KO, force measurements, histology, electron microscopy, Ca2+ homeostasis, ASO treatment\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — faithful mammalian genetic model with multiple orthogonal phenotype assays and therapeutic epistasis rescue\",\n      \"pmids\": [\"34371181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cavin4 directly interacts with Bin1 (Cavin4b in zebrafish) and localizes to T-tubules; loss of Cavin4 causes aberrant T-tubule maturation and accumulation of interconnected caveolae within T-tubules, impairing Ca2+ response; Cavin4 is proposed to remodel T-tubule membrane by recycling caveolar components.\",\n      \"method\": \"Direct interaction assay (Cavin4b-Bin1), Cavin4 KO mouse and zebrafish, confocal microscopy, Ca2+ imaging\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction assay with genetic KO in two organisms and functional Ca2+ readout, single lab\",\n      \"pmids\": [\"34633413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LOAD-associated BIN1 coding variants (rs754834233, rs138047593) reduce BIN1 interaction with BACE1 and fail to rescue BACE1 recycling impaired by Bin1 knockdown; BIN1 normally promotes BACE1 recycling from early endosomes, and its loss increases intracellular Aβ42 by enabling BACE1 cleavage of APP in enlarged early endosomes.\",\n      \"method\": \"Co-immunoprecipitation of BIN1-BACE1, early endosome morphology assay, Aβ ELISA, BACE1 recycling assay, BIN1 variant overexpression/knockdown rescue\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP interaction with specific disease variants and functional endocytic recycling assay, single lab\",\n      \"pmids\": [\"34375641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"BIN1 isoform 1 (neuronal) overexpression causes early endosome accumulation and neurodegeneration in Drosophila and human induced neurons; BIN1 KO narrows early endosomes; isoform 1 rescues BIN1-KO early endosome phenotype but isoform 9 does not, identifying isoform-specific control of early endosome size.\",\n      \"method\": \"Drosophila overexpression, hiN and cerebral organoid BIN1 KO, endosome morphometry, isoform rescue experiments\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO and isoform rescue in two human cell models plus Drosophila, single lab\",\n      \"pmids\": [\"34998435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Neuronal BIN1 isoform 1 (BIN1V1) but not isoform 9 (BIN1V9) downregulates BACE1-mediated APP processing and Aβ generation in a RIN3-dependent manner; BIN1V1 delays APP (but not BACE1) endocytosis into early endosomes, spatially separating APP from BACE1; RIN3 sequesters BIN1V1 via CLAP domain into RAB5+ endosomes.\",\n      \"method\": \"Confocal microscopy, Western blot, Aβ ELISA, surface biotinylation APP internalization assay, FACS-enriched cell populations, isoform transfection\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific functional assays with APP internalization and Aβ measurement, single lab\",\n      \"pmids\": [\"35241726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Microglial BIN1 regulates proinflammatory and disease-associated microglial activation; BIN1 loss impairs type 1 interferon responses in microglia, particularly upregulation of Ifitm3; Bin1 regulates transcription factors PU.1 and IRF1, and loss of microglial Bin1 in vivo alters disease-associated gene expression and CX3CR1 signaling.\",\n      \"method\": \"siRNA Bin1 knockdown in primary microglia, Cre-lox microglia-specific conditional KO, NanoString transcriptomics, flow cytometry, cytokine measurement\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional microglial KO in vivo with transcriptomic and cytokine readouts, single lab with orthogonal in vitro and in vivo approaches\",\n      \"pmids\": [\"35526014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BIN1, MTM1, and DNM2 have balanced roles in T-tubule growth in cardiomyocytes: all four cardiac BIN1 isoforms induce tubulation but with different geometries; high MTM1 (phosphoinositide phosphatase) levels are necessary for BIN1-induced tubulation (without direct binding to cardiac BIN1 isoforms lacking exon 11); high DNM2 levels are inhibitory for T-tubule formation despite DNM2 binding all four BIN1 isoforms and co-localizing at Z-lines.\",\n      \"method\": \"Developing mouse cardiomyocytes, gene-modified HL-1 and hiPSC-derived cardiomyocytes, confocal/Airyscan microscopy, RT-qPCR, Western blot, Ca2+ recording, co-IP\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple isoforms characterized with co-IP and tubulation assays, genetic and pharmacological perturbations, single lab\",\n      \"pmids\": [\"37139790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Bin1 loss elevates STAT1- and NF-κB-dependent expression of IDO in tumor cells, promoting immune escape from T cell-dependent antitumor immunity; Bin1 knockout studies establish that Bin1 loss upregulates IDO expression.\",\n      \"method\": \"Mouse knockout studies, STAT1/NF-κB pathway analysis, IDO expression measurement, immune escape assays in MMTV-Neu mice\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO mouse with defined pathway analysis (STAT1/NF-κB-IDO), single lab\",\n      \"pmids\": [\"15711557\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BIN1 (Amphiphysin II) is a multi-domain BAR adaptor protein whose crescent-shaped N-BAR domain senses and generates membrane curvature in a PI(4,5)P2-regulated, autoinhibited manner; it scaffolds T-tubule biogenesis in muscle and heart by recruiting Cav1.2 via microtubule-tethered delivery and promoting N-WASP-dependent actin polymerization, while negatively regulating Dynamin 2 GTPase activity; in the nucleus it suppresses MYC transactivation, PARP1 catalytic activity, and ATM/E2F1-driven DNA repair to maintain cisplatin sensitivity; its SH3 domain directly binds Tau's proline-rich domain in a phosphorylation-regulated manner, and in neurons it controls presynaptic vesicle dynamics, AMPA receptor trafficking, and early endosome size to modulate Aβ generation and tau spreading relevant to Alzheimer's disease.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BIN1 (Amphiphysin II) is a multi-domain membrane-remodeling adaptor whose N-BAR domain senses and generates membrane curvature in an autoinhibited, phosphoinositide-regulated manner [#29, #12]. Its membrane-deforming activity is gated by an intramolecular interaction between its polybasic exon10 region and the SH3 domain, which is relieved by PI(4,5)P2 binding or by SH3 ligands such as PxxP-containing dynamin [#10, #29]; cryo-EM shows the N-terminal amphipathic helix H0 nucleates cooperative N-BAR polymerization on membrane tubes [#31]. Through PI(4,5)P2 clustering BIN1 recruits and negatively regulates dynamin 2 GTPase activity, a relationship essential for T-tubule biogenesis: BIN1 scaffolds T-tubule membranes in skeletal and cardiac muscle, recruits Cav1.2 via microtubule-tethered delivery and drives N-WASP-dependent actin folding of T-tubule membranes for excitation-contraction coupling [#27, #46, #18, #26]. Genetic loss of BIN1 causes perinatal cardiomyopathy in mice [#9] and muscle-specific deletion recapitulates centronuclear myopathy that is rescued by lowering DNM2 [#47, #34], while disease-linked missplicing (myotonic dystrophy via MBNL1) and CNM coding mutations impair its membrane-tubulating activity [#21, #30]. In the nucleus, BIN1 binds the MYC transactivation domain through its SH3 and MYC-binding domains to suppress MYC-driven transformation and to engage apoptotic and tumor-suppressive programs [#0, #5, #11, #24]; it also binds and inhibits PARP1 and restrains E2F1/ATM-driven DNA repair to maintain cisplatin sensitivity [#22, #43]. In neurons BIN1 controls presynaptic vesicle dynamics, synaptic transmission and AMPA receptor trafficking [#41, #44], and its SH3 domain directly binds the tau proline-rich domain in a phosphorylation- and conformation-regulated manner linking it to tauopathy and Alzheimer's disease [#25, #36, #38].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established BIN1's founding identity as a MYC-interacting tumor suppressor, defining a nuclear/oncogenic axis distinct from its later membrane roles.\",\n      \"evidence\": \"Interaction screen and growth-suppression assays against MYC-transformed cells\",\n      \"pmids\": [\"8782822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the binding domain or structural basis\", \"Did not connect MYC suppression to membrane biology\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Localized BIN1 to neuronal axon initial segments/nodes and muscle T-tubules, and identified it as a short-lived nuclear phosphoprotein mislocalized in tumors, foreshadowing dual nuclear and membrane functions.\",\n      \"evidence\": \"Immunofluorescence and subcellular fractionation in brain/muscle; pulse-chase and immunostaining in normal vs tumor cells\",\n      \"pmids\": [\"9182667\", \"9242458\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the mechanism of T-tubule targeting\", \"Functional consequence of tumor relocalization unresolved\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showed alternative splicing controls MYC-binding capacity and that MyoD drives muscle expression, introducing isoform switching as a core regulatory principle.\",\n      \"evidence\": \"Exon mapping, promoter reporter, cell-type RT-PCR\",\n      \"pmids\": [\"9395479\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional impact of each splice variant not fully tested\", \"Single-lab promoter analysis\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Resolved that BIN1 suppresses growth by both MYC-dependent transactivation inhibition and MYC-independent mechanisms, and that brain exon 12A inclusion abolishes tumor-suppressor and apoptotic activity, linking splicing to oncogenic escape.\",\n      \"evidence\": \"Co-IP, transcriptional reporters, transformation and apoptosis assays with isoform comparison\",\n      \"pmids\": [\"10380878\", \"10449755\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MYC-independent effectors not identified\", \"Mechanism by which exon 12A blocks function unclear at the time\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined a caspase-independent, BAR-domain-dependent cell death program engaged by BIN1, distinguishing its apoptotic effect from canonical pathways.\",\n      \"evidence\": \"Domain mutagenesis and pharmacological inhibitors in cell death assays\",\n      \"pmids\": [\"11032017\", \"11306501\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular executioners of this death program unknown\", \"Single-lab characterization\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Genetic knockout revealed that BIN1's essential in vivo role is cardiac, not endocytic, redirecting the field from a presumed generic endocytosis function toward muscle membrane organization.\",\n      \"evidence\": \"Constitutive Bin1 knockout mouse with histology, EM, and endocytosis/phagocytosis assays\",\n      \"pmids\": [\"12773571\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Perinatal lethality limited adult analysis\", \"Molecular cause of cardiomyopathy not yet defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified the phosphoinositide-gated intramolecular exon10-SH3 mechanism, explaining how BIN1's SH3-ligand binding (including dynamin) is regulated by PI(4,5)P2.\",\n      \"evidence\": \"In vitro binding, PI(4,5)P2 titration, T-tubule formation assay\",\n      \"pmids\": [\"15483625\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how this couples to membrane curvature generation\", \"Single-lab biochemistry\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Connected BIN1 loss to tumor immune escape via STAT1/NF-kB-driven IDO upregulation, broadening its tumor-suppressor role to immune evasion.\",\n      \"evidence\": \"Knockout mouse studies with pathway analysis in MMTV-Neu model\",\n      \"pmids\": [\"15711557\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between BIN1 and IDO transcription unresolved\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Provided structural and biochemical definition of the BIN1 SH3-MYC interaction and showed phosphorylation of MYC Ser62 and intramolecular polyproline-SH3 binding disable it in tumor isoforms.\",\n      \"evidence\": \"NMR structure, SPR, biochemical binding\",\n      \"pmids\": [\"15992821\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of Ser62 regulation not tested\", \"Dynamics of complex incompletely described\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Crystal and interaction structures of the BAR domain and an SH3-MYC complex provided the architectural basis for membrane curvature and protein scaffolding.\",\n      \"evidence\": \"X-ray crystallography of BAR domain; yeast two-hybrid/Co-IP and infectivity for HCV NS5A binding\",\n      \"pmids\": [\"17059209\", \"16530520\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Convex-face protein partners not all identified\", \"How curvature is dynamically tuned in cells unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linked BIN1 membrane tubulation to the cytoskeleton and endocytic recycling, showing BAR-domain binding to CLIP-170, cooperative tubulation with EHD1/RME-1, and SH3 scaffolding of sarcomere components.\",\n      \"evidence\": \"Co-IP, GST pulldown, RNAi, in vitro reconstitution with purified AMPH-1/RME-1, dominant-negative expression\",\n      \"pmids\": [\"19004523\", \"19915558\", \"19633357\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy among microtubule, actin and recycling functions unclear\", \"Tissue specificity of each interaction not resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placed BIN1 downstream of E2F1 as a transcriptional target mediating DNA-damage apoptosis independent of p53, integrating it into stress-response signaling.\",\n      \"evidence\": \"Promoter reporter, ChIP, siRNA, DNA damage apoptosis assays\",\n      \"pmids\": [\"19629135\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apoptotic effectors downstream of BIN1 unidentified\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the cardiac mechanism by which BIN1 scaffolds T-tubules to deliver Cav1.2 via microtubule tethering, establishing its role in calcium handling.\",\n      \"evidence\": \"Immunogold EM, Co-IP, surface biotinylation, live-cell TIRF, shRNA knockdown\",\n      \"pmids\": [\"20169111\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address skeletal muscle EC coupling\", \"Microtubule-membrane tether composition incompletely defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended T-tubule scaffolding to skeletal muscle EC coupling and human heart failure, and identified MBNL1-dependent missplicing as a disease mechanism, plus a PARP1/MYC axis controlling cisplatin resistance.\",\n      \"evidence\": \"In vivo shRNA electroporation with electrophysiology; failing-heart tissue with multi-species knockdown; MBNL1 RNA-binding and transgenic mouse splicing model; PARP1 activity and binding assays\",\n      \"pmids\": [\"21984944\", \"22138472\", \"21623381\", \"21447800\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How missplicing produces functional loss structurally not fully defined\", \"PARP1 nuclear and membrane roles not reconciled\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established direct BIN1-Tau interaction and modifier genetics, opening the neurodegeneration axis, alongside biophysical characterization of the disordered MYC-BIN1 complex.\",\n      \"evidence\": \"Co-IP, co-localization, Drosophila tau-toxicity suppression; NMR/SPR of MYC transactivation domain\",\n      \"pmids\": [\"23399914\", \"22457068\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Domain and residue-level basis of Tau binding not yet defined\", \"Directionality of BIN1 effect on tau toxicity in mammals unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapped the BIN1 SH3-Tau proline-rich-domain interaction and its regulation by Tau Thr231 phosphorylation, defining a phospho-switch relevant to tauopathy.\",\n      \"evidence\": \"GST pulldown, NMR, primary neuron co-localization, phospho-specific analysis\",\n      \"pmids\": [\"26395440\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular consequence of disrupted SH3-PRD binding not yet measured\", \"Link to pathological aggregation unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided a comprehensive mechanistic and structural model of BIN1 membrane action: autoinhibition relieved by PI(4,5)P2, PI(4,5)P2 clustering to recruit dynamin, N-WASP-dependent T-tubule folding for electrical insulation, and CNM-mutant defects in tubulation.\",\n      \"evidence\": \"In vitro membrane deformation and dynamin recruitment assays, cardiac-specific KO with superresolution and electrophysiology, liposome tubulation of CNM mutants\",\n      \"pmids\": [\"25487648\", \"25350771\", \"26487375\", \"24836577\", \"25332206\", \"24755653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coupling between autoinhibition release and dynamin regulation in vivo not fully resolved\", \"Distinct CNM mutant mechanisms not unified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Tied beta-adrenergic signaling and Rab8/EHBP1L1-dependent vesicular transport to BIN1, showing dynamic recruitment of phospho-RyR2 to dyads and apical trafficking roles.\",\n      \"evidence\": \"Co-IP, superresolution imaging, Bin1 heterozygous mice; binding assays and EHBP1L1-KO mouse in epithelia\",\n      \"pmids\": [\"26733606\", \"26833786\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling input controlling BIN1 redistribution incompletely mapped\", \"Generalizability of Rab8 complex beyond epithelia unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated genetically that BIN1's key muscle function is negative regulation of DNM2, with Dnm2 reduction rescuing Bin1-null lethality, and characterized BAR-domain actin stabilization relevant to tau.\",\n      \"evidence\": \"Bin1-/- Dnm2+/- epistasis mice with in vitro GTPase assay; in vitro actin binding/bundling plus Drosophila tauopathy KD\",\n      \"pmids\": [\"29130937\", \"28893863\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Isoform-specific DNM2 regulation not fully resolved\", \"Role of actin stabilization in disease unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved the residue-level NMR structure of the BIN1 SH3-Tau interface and quantified how multisite Tau phosphorylation weakens binding and unmasks the intramolecular SH3-CLAP interaction.\",\n      \"evidence\": \"NMR, SPR, competition binding; BIN1 expression in hESC-cardiomyocytes for T-tubule induction\",\n      \"pmids\": [\"30487734\", \"30353632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological role of competition between Tau and CLAP unclear\", \"In vivo consequence of phospho-weakening untested here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined neuronal and glial BIN1 functions: presynaptic vesicle dynamics and learning, calcineurin-controlled conformational gating of Tau binding, microglial control of Tau spreading, an LVGCC-Tau hyperexcitability axis, and the negative result that neuronal BIN1 does not regulate Abeta in vivo.\",\n      \"evidence\": \"Conditional neuronal/microglial KO with behavior, electrophysiology, EM, NMR conformational analysis, EV-Tau quantification, MEA recordings, and 5XFAD amyloid analysis\",\n      \"pmids\": [\"31065832\", \"31263146\", \"32160554\", \"32657270\", \"30692199\", \"30733337\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Sex-specific microglial effects not mechanistically explained\", \"Reconciliation of pro- and anti-pathogenic neuronal roles incomplete\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Expanded synaptic roles to postsynaptic AMPA receptor trafficking via Arf6/GluA1 complexes and clarified excitability and tau-background mortality phenotypes of neuronal Bin1 loss.\",\n      \"evidence\": \"Superresolution SIM, Co-IP, surface biotinylation, electrophysiology, conditional KO with transcriptomics, GTPase reconstitution assay\",\n      \"pmids\": [\"30967682\", \"31408457\", \"33187981\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct structural basis of BIN1-Arf6-GluA1 complex undefined\", \"Integration of pre- and postsynaptic functions unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Validated BIN1-DNM2 as a therapeutic axis in centronuclear myopathy, identified Cavin4 as a T-tubule partner, defined endosome-based control of Abeta generation, and linked LOAD coding variants to impaired BACE1 recycling.\",\n      \"evidence\": \"Muscle-specific KO with DNM2 ASO rescue; Cavin4 KO in mouse and zebrafish; Co-IP of BIN1-BACE1 with variants and endosome/Abeta assays\",\n      \"pmids\": [\"34371181\", \"34633413\", \"34375641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cardiac vs skeletal DNM2 isoform regulation differences unresolved\", \"Mechanistic link between endosome enlargement and Abeta incompletely defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established isoform-specific neuronal control of early endosome size and BACE1/APP spatial separation (RIN3-dependent), and defined microglial BIN1 control of interferon and disease-associated activation programs.\",\n      \"evidence\": \"Drosophila and human neuron/organoid KO with isoform rescue, endosome morphometry, APP internalization and Abeta assays; microglial conditional KO with transcriptomics and cytokine measurement\",\n      \"pmids\": [\"34998435\", \"35241726\", \"35526014\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why isoform 1 but not isoform 9 controls endosome size mechanistically unclear\", \"In vivo contribution of microglial interferon regulation to AD pathology unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved the balanced cardiac roles of BIN1, MTM1, and DNM2 in tuning T-tubule growth geometry, integrating phosphoinositide phosphatase and fission machinery with BIN1 isoform-specific tubulation.\",\n      \"evidence\": \"Developing cardiomyocytes, gene-modified HL-1 and hiPSC-CMs, Airyscan microscopy, Co-IP, Ca2+ recording\",\n      \"pmids\": [\"37139790\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative stoichiometry balancing the three regulators in vivo undefined\", \"Cardiac vs skeletal differences in MTM1 dependence unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How BIN1's distinct compartmentalized functions—nuclear MYC/PARP1/E2F1 tumor suppression, muscle T-tubule scaffolding, and neuronal endosomal/synaptic/tau roles—are coordinately partitioned by isoform expression, phosphorylation, and conformational state across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking isoform/phospho-state to compartment-specific function\", \"Causal contribution of BIN1 variants to Alzheimer's pathogenesis mechanism still debated across opposing neuronal/microglial datasets\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [10, 29, 27]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [10, 18, 44]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [27, 46, 34, 22]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [35, 14, 16]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [12, 31, 26]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 18, 20, 27]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 4, 22]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [15, 49, 50, 51]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [14, 25, 35]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [19, 26, 47, 18]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [15, 33, 49, 27]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [21, 26, 47, 53]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [22, 43]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [41, 44, 40]}\n    ],\n    \"complexes\": [\"BIN1-DNM2 membrane fission complex\", \"T-tubule/dyad scaffold (BIN1-Cav1.2-RyR2)\", \"BIN1-EHD1/RME-1 recycling tubule\", \"EHBP1L1-Rab8-BIN1-dynamin complex\"],\n    \"partners\": [\"MYC\", \"DNM2\", \"Tau (MAPT)\", \"PARP1\", \"E2F1\", \"CLIP-170\", \"BACE1\", \"Cav1.2 (CACNA1C)\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}