{"gene":"VAPB","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2004,"finding":"VAPB (VAP-B/ALS8) is an intracellular membrane protein whose MSP domain mutation P56S causes motor neuron disease; the protein associates with microtubules and functions in membrane transport.","method":"Genetic mapping, missense mutation identification, haplotype analysis in affected families","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — genetic identification with functional inference, replicated across multiple kindreds but no direct biochemical mechanism experiment in this paper","pmids":["15372378"],"is_preprint":false},{"year":2007,"finding":"VAPB (and VAPA) interact with lipid-binding proteins carrying FFAT motifs and target them to the cytosolic surface of the ER. The P56S mutation causes aggregation of mutant VAPB in immobile tubular ER clusters, perturbs FFAT-motif binding, and traps endogenous wild-type VAPB in mutant aggregates. Reduction of VAP by shRNA in primary neurons causes Golgi dispersion and cell death.","method":"Immunofluorescence, FRAP, co-immunoprecipitation, shRNA knockdown in primary neurons, mass spectrometry","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (FRAP, Co-IP, shRNA, live imaging) establishing localization, binding, and functional consequence","pmids":["17804640"],"is_preprint":false},{"year":2006,"finding":"Wild-type VAPB promotes the unfolded protein response (UPR) via the IRE1/XBP1 pathway; siRNA knockdown of VAPB attenuates UPR. The P56S mutation causes VAPB to form insoluble aggregates in non-ER fractions, abolishing its ability to mediate UPR, and the mutant protein induces co-aggregation and mislocalization of co-expressed wild-type VAPB.","method":"siRNA knockdown, overexpression, UPR reporter assays, fractionation, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (siRNA, reporter assay, fractionation) in one study establishing UPR function","pmids":["16891305"],"is_preprint":false},{"year":2008,"finding":"The MSP domains of VAP proteins (VAPB/ALS8, Drosophila VAP33, C. elegans VPR-1) are cleaved and secreted as ligands for Eph receptors. The P58S mutation in Drosophila VAP33 prevents MSP domain secretion and leads to ubiquitination, ER inclusion accumulation, and an unfolded protein response.","method":"In vivo cleavage/secretion assays in Drosophila and C. elegans, Eph receptor binding assays, genetic epistasis, ubiquitination assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstitution of secretion, receptor binding, and mutagenesis across multiple model organisms","pmids":["18555774"],"is_preprint":false},{"year":2008,"finding":"The MSP domain of VAPA and VAPB interacts with the ER-localized transcription factor ATF6. Overexpression of VAPB or VAPB(P56S) attenuates ATF6-regulated transcription, with the mutant being a more potent inhibitor.","method":"Co-immunoprecipitation, transcriptional reporter assays, overexpression","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus functional reporter assay, single lab","pmids":["18263603"],"is_preprint":false},{"year":2008,"finding":"VAPB function is required for transport of nucleoporins and emerin to the nuclear envelope; VAPB P56S mutation sequesters these proteins in dilated cytoplasmic ERGIC membranes. FFAT motif overexpression antagonizes mutant VAPB and restores nuclear envelope transport. Knockdown of endogenous VAPB recapitulates the nuclear envelope transport defect.","method":"Overexpression, siRNA knockdown, immunofluorescence, ERGIC marker co-localization","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal functional rescue and knockdown experiments, single lab, two orthogonal approaches","pmids":["22454507"],"is_preprint":false},{"year":2008,"finding":"VAPA inhibits ER-to-Golgi transport and lateral diffusion of membrane proteins via stable association with microtubules; overexpression of the FFAT motif restores transport and lateral diffusion, and disrupts VAP-microtubule association. VAPB P56S forms large ER aggregates that are resolved by FFAT overexpression.","method":"In vitro ER vesicle budding assay, live-cell imaging, microtubule co-sedimentation, FFAT peptide competition","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of vesicle budding plus live imaging and biochemical disruption assays","pmids":["18713837"],"is_preprint":false},{"year":2005,"finding":"Human VAPB interacts with HCV NS5A and NS5B via its MSP domain and coiled-coil domain respectively, forms homo- and heterodimers with VAPA through the transmembrane domain, co-localizes with NS5A at the ER and Golgi, and is required for HCV RNA replication; specific anti-VAPB antibody suppresses HCV RNA replication in a cell-free assay.","method":"Yeast two-hybrid, co-immunoprecipitation, mutation analysis, siRNA knockdown, cell-free replication assay, immunofluorescence","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including cell-free replication assay, Co-IP with domain mutants, and siRNA","pmids":["16227268"],"is_preprint":false},{"year":2010,"finding":"VAP-B oligomerization is primarily mediated by its coiled-coil domain; the GXXXG motif in the transmembrane domain mediates TM self-association but is insufficient for oligomerization. The P56S mutation induces conformational changes in the MSP domain exposing hydrophobic patches, which enhances oligomerization and aggregation without directly affecting FFAT binding.","method":"Mutagenesis, size-exclusion chromatography, co-immunoprecipitation, cell-based aggregation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with biochemical assays to dissect structural requirements, single lab","pmids":["20207736"],"is_preprint":false},{"year":2009,"finding":"P56S-VAPB is a loss-of-function mutant confirmed by yeast inositol-auxotrophy assay. Wild-type VAPB preferentially interacts with P56S-VAPB through the MSP domain (in addition to TM domain interactions), leading to recruitment of wild-type VAPB into cytosolic aggregates and attenuation of UPR function. P56S-VAPB expression increases vulnerability of NSC34 motoneuronal cells to ER stress-induced death.","method":"Yeast inositol-auxotrophy assay, co-immunoprecipitation, cell viability assays","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vivo yeast functional assay plus co-IP domain mapping, single lab","pmids":["19183264"],"is_preprint":false},{"year":2009,"finding":"P56S-VAPB inserts post-translationally into ER membranes identically to wild-type VAPB but rapidly clusters to form inclusions that remain continuous with the ER. Ultrastructural analysis reveals the inclusions represent a novel form of organized smooth ER (OSER) consisting of parallel cisternae interleaved by a ~30 nm electron-dense cytosolic layer.","method":"Cell-free translocation assays, confocal imaging, electron microscopy","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cell-free biochemical assay combined with ultrastructural EM analysis","pmids":["20008544"],"is_preprint":false},{"year":2011,"finding":"VAPB interacts with the outer mitochondrial membrane protein PTPIP51. VAPB is a mitochondria-associated membrane (MAM) protein. Loss of either VAPB or PTPIP51 perturbs mitochondrial Ca2+ uptake following ER store release. The P56S mutant has altered binding to PTPIP51 and increases mitochondrial Ca2+ uptake.","method":"Co-immunoprecipitation, fractionation (MAM isolation), Ca2+ imaging with mitochondria-targeted cameleon, siRNA knockdown","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, subcellular fractionation, functional Ca2+ measurements with loss-of-function","pmids":["22131369"],"is_preprint":false},{"year":2011,"finding":"VAPB undergoes proteolytic processing in neurons in a developmentally regulated manner; the C-terminal fragment remains membrane-associated with distinct localization from full-length protein. The P56S mutant is resistant to neuronal proteolysis.","method":"Western blotting in rat brain fractions during postnatal development, primary neuronal cultures, HEK293 overexpression","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — biochemical fractionation across development and cell types, single lab","pmids":["21275991"],"is_preprint":false},{"year":2012,"finding":"Restructured ER generated by P56S-VAPB is cleared by the proteasome. Shortly after synthesis, mutant VAPB forms small polyubiquitinated clusters that congregate in the juxtanuclear region. Clearance involves p97/VCP ATPase activity (dominant-negative p97 stabilizes mutant VAPB). Clearance does not involve macro-autophagy.","method":"Stable inducible cell lines (Tet-Off), proteasome inhibitors, autophagy inhibitors, dominant-negative p97, pulse-chase, microinjection","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal pharmacological and genetic approaches in inducible system","pmids":["22611258"],"is_preprint":false},{"year":2012,"finding":"VAPB secreted MSP domain (vMSP) acts on Lar-like protein-tyrosine phosphatase and Roundabout (Robo) growth cone guidance receptors on striated muscle, promoting Arp2/3-dependent actin remodeling and mitochondrial localization to actin-rich muscle I-bands. VAPB mutants have mitochondrial localization, morphology, mobility, and fission/fusion defects suppressible by Lar-like receptor or Arp2/3 inactivation.","method":"Genetic epistasis in C. elegans and Drosophila, receptor binding assays, mitochondrial imaging, actin remodeling assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in two model organisms with receptor binding and cellular phenotype rescue","pmids":["22264801"],"is_preprint":false},{"year":2013,"finding":"VAPB interacts with YIF1A (an ER-Golgi recycling protein) via transmembrane regions. VAPB is required for intracellular membrane trafficking into dendrites and normal dendritic morphology. P56S-VAPB recruits YIF1A into ER clusters, displacing it from ERGIC compartments.","method":"Co-immunoprecipitation, yeast two-hybrid, immunofluorescence in hippocampal neurons, siRNA knockdown","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus neuronal localization and functional knockdown","pmids":["23736259"],"is_preprint":false},{"year":2013,"finding":"VAPB-P56S inclusions in transgenic mouse motor neurons are immunoreactive for ERAD pathway factors (p97/VCP, Derlin-1, BAP31) and represent a reversible ER quality control compartment. Proteasome inhibition increases inclusion size; knockdown of TEB4 (ERAD E3 ligase) reduces inclusion size; BAP31 knockdown increases inclusion size.","method":"Immunohistochemistry, transgenic mouse model, siRNA knockdown, proteasome inhibition in primary neuron cultures","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological manipulation with defined inclusion phenotypes, single lab","pmids":["24252306"],"is_preprint":false},{"year":2014,"finding":"VAPB interacts with the mitochondrial protein PTPIP51 to tether ER to mitochondria. TDP-43 perturbs ER-mitochondria interactions by disrupting the VAPB-PTPIP51 interaction via activation of GSK-3β. Disrupted VAPB-PTPIP51 interaction is accompanied by altered cellular Ca2+ homeostasis.","method":"Co-immunoprecipitation, proximity ligation assay, electron microscopy, Ca2+ measurements, GSK-3β inhibitors/activators, siRNA knockdown","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including EM, PLA, Ca2+ imaging, pharmacological and genetic modulation","pmids":["24893131"],"is_preprint":false},{"year":2014,"finding":"VAPB interacts with the peroxisomal membrane protein ACBD5 to mediate peroxisome-ER associations. Loss of this interaction perturbs peroxisome membrane expansion and increases peroxisome movement.","method":"Co-immunoprecipitation, proximity ligation assay, electron microscopy, live imaging of peroxisome dynamics, siRNA knockdown","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, EM, live imaging, and functional loss-of-function in one study","pmids":["28108524"],"is_preprint":false},{"year":2014,"finding":"VAPB interacts with FAF1 (a p97 ATPase cofactor) via a non-canonical FFAT-like motif in FAF1, thereby linking VAPB to p97 function. VAPB also interacts with ASNA1 (TRC complex subunit) via a similar FFAT-like motif. Proteasome inhibition increases ubiquitinated species in VAPB immunoprecipitates and increases FAF1/p97 binding. FAF1 siRNA reduces VAPB interaction with ubiquitinated proteins.","method":"Co-immunoprecipitation, in vitro binding assays with recombinant proteins, siRNA knockdown, FFAT motif mutagenesis","journal":"BMC biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro binding with recombinant proteins plus cellular Co-IP and siRNA validation","pmids":["24885147"],"is_preprint":false},{"year":2014,"finding":"Expression of the C. trachomatis effector IncD on the inclusion membrane causes massive recruitment of CERT lipid transfer protein via its PH domain, which in turn recruits VAPB to the inclusion; the CERT-VAPB interaction at the inclusion relies on the FFAT domain of CERT.","method":"Conditional IncD expression in C. trachomatis, immunofluorescence, domain deletion analysis","journal":"Infection and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic conditional expression system plus domain-specific mutants, single lab","pmids":["24595143"],"is_preprint":false},{"year":2016,"finding":"ALS/FTD-associated mutant FUS disrupts the VAPB-PTPIP51 interaction and ER-mitochondria associations via activation of GSK-3β, impairing mitochondrial Ca2+ uptake and ATP production.","method":"Co-immunoprecipitation, proximity ligation assay, Ca2+ imaging, ATP assays, GSK-3β inhibitors","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, PLA, Ca2+ imaging, ATP measurement) in one study","pmids":["27418313"],"is_preprint":false},{"year":2017,"finding":"The VAPB-PTPIP51 ER-mitochondria tethers regulate autophagy: overexpression of VAPB or PTPIP51 (tightening contacts) impairs autophagosome formation, while siRNA loss stimulates it. An artificial ER-mitochondria linker rescues the effects of VAPB/PTPIP51 siRNA, confirming the tethering function mediates the autophagic regulation. The mechanism involves VAPB-PTPIP51-mediated delivery of Ca2+ to mitochondria.","method":"siRNA knockdown, overexpression, artificial tether rescue, autophagy flux assays, Ca2+ imaging","journal":"Current biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — orthogonal genetic approaches including artificial tether rescue, Ca2+ imaging, and autophagy flux measurement","pmids":["28132811"],"is_preprint":false},{"year":2017,"finding":"α-Synuclein binds directly to VAPB, and overexpression of wild-type or familial PD mutant α-synuclein disrupts the VAPB-PTPIP51 tethers, loosening ER-mitochondria associations and disrupting Ca2+ exchange and mitochondrial ATP production.","method":"Co-immunoprecipitation, proximity ligation assay, Ca2+ imaging, mitochondrial ATP measurements, iPSC-derived neurons from PD patients","journal":"Acta neuropathologica","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, PLA, Ca2+ imaging, ATP assay, and patient iPSC-derived neuron validation","pmids":["28337542"],"is_preprint":false},{"year":2017,"finding":"Murine norovirus requires VAPA and VAPB for replication; viral NS1/2 protein contains an FFAT motif mimic that binds the MSP domain of VAPA/VAPB. Mutations in NS1 disrupting VAPB/VAPA interaction inhibit viral replication.","method":"Genetic deletion of VAPA/VAPB, structural analysis (FFAT mimic identification), mutagenesis, viral replication assays","journal":"mBio","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — genetic KO plus structural analysis and mutagenesis of binding interface, single lab","pmids":["28698274"],"is_preprint":false},{"year":2018,"finding":"Kv2.1 and Kv2.2 voltage-gated K+ channels interact with VAPA and VAPB at ER-PM junctions via a non-canonical phosphorylation-dependent FFAT motif in the Kv2 C-terminus. VAP binding recruits Kv2 channels to ER-PM contact sites. VAPA knockout reduces Kv2.1 clustering.","method":"Proximity-based biotinylation (BioID), FRET, siRNA knockdown, colocalization assays, CD4-chimera domain mapping, KO cells","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (BioID, FRET, siRNA, KO, domain mapping) in one study","pmids":["29941597"],"is_preprint":false},{"year":2018,"finding":"VAPB (and VAPA) are identified as prominent Kv2.1-associated proteins in brain; VAPs are recruited to ER-PM junctions by Kv2.1 or Kv2.2 expression. The VAPB-Kv2 association relies on the FFAT-binding domain on VAPA/VAPB and a non-canonical phosphorylation-dependent FFAT motif (PRC/clustering domain) on Kv2. VAPA knockout reduces Kv2.1 clustering in mammalian cells.","method":"Affinity immunopurification + mass spectrometry from brain, Kv2.1 KO mice, VAPA KO cells, multiplex immunolabeling in brain sections","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — mass spectrometry from brain tissue, KO validation, in situ co-localization in neurons","pmids":["30012696"],"is_preprint":false},{"year":2018,"finding":"VAPB is an essential modulator of HCN1 and HCN2 pacemaker channels; VAPB significantly increases HCN2 currents and surface expression and influences dendritic distribution of HCN2 in neurons. VAPB-deficient zebrafish and VAPB-/- mice exhibit cardiac bradycardia, demonstrating a physiological role for VAPB in cardiac pacemaker function.","method":"Electrophysiology (patch clamp), surface expression assays, VAPB KO zebrafish and mice, ECG recordings","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — electrophysiology plus KO animal models in two species with defined physiological phenotypes","pmids":["29879376"],"is_preprint":false},{"year":2019,"finding":"VAPB and PTPIP51 localize to and form contacts at synapses. Stimulating neuronal activity increases ER-mitochondria contacts and VAPB-PTPIP51 interaction. siRNA loss of VAPB or PTPIP51 perturbs synaptic activity and dendritic spine morphology.","method":"Immunofluorescence, proximity ligation assay, synaptic electrophysiology, siRNA knockdown, spine morphology analysis","journal":"Acta neuropathologica communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — PLA, electrophysiology, and morphological analysis with genetic loss-of-function","pmids":["30841933"],"is_preprint":false},{"year":2019,"finding":"VAPB localizes to the inner nuclear membrane (INM) as demonstrated by immunoelectron microscopy. Proximity proteomics (APEX2-SILAC targeted to VAPB) identified emerin, TMEM43, and ELYS as potential VAPB interaction partners at the INM and nuclear pore complex.","method":"Immunoelectron microscopy, rapamycin-dependent APEX2 proximity labeling, SILAC mass spectrometry","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — immunoEM plus proximity proteomics, single lab; interactions not confirmed by orthogonal methods","pmids":["31519755"],"is_preprint":false},{"year":2019,"finding":"VAPB facilitates nuclear egress of HSV-1; a subpopulation of VAPB is present in the nuclear membrane co-localizing with viral pUL34. VAPB knockdown significantly reduces both cell-associated and supernatant virus titers and reduces cytoplasmic accumulation of virus particles while increasing nuclear encapsidated viral DNA. Immunogold-EM confirms VAPB associated with primary enveloped HSV-1 particles.","method":"siRNA knockdown, viral titer assays, immunofluorescence, immunogold electron microscopy","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA plus immunoEM showing VAPB with virions, single lab","pmids":["30717447"],"is_preprint":false},{"year":2018,"finding":"Loss of VAPB induces upregulation of beclin 1 at the transcriptional level, promoting LC3 conversion, autophagosome formation, and autophagic flux including degradation of p62 and neurodegenerative disease proteins. VAPB overexpression inhibits these processes.","method":"siRNA knockdown, overexpression, Western blot for autophagy markers (LC3, p62, beclin 1), autophagic flux assays","journal":"Neuroscience bulletin","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — genetic gain- and loss-of-function with multiple autophagy markers, single lab","pmids":["30143980"],"is_preprint":false},{"year":2022,"finding":"Peroxisome-ER associations via the ACBD5-VAPB tether are regulated by phosphorylation of the FFAT-like motif of ACBD5. GSK3β regulates ACBD5-VAPB binding and thus peroxisome-ER contact sites. Phosphorylation sites in the flanking regions and core of the FFAT-like motif differentially alter VAPB interaction.","method":"Co-immunoprecipitation, phosphatase treatment, site-directed mutagenesis of phosphorylation sites, GSK3β inhibitors/activators, proximity ligation assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis of phosphorylation sites, kinase manipulation, and multiple binding assays in one study","pmids":["35019937"],"is_preprint":false},{"year":2022,"finding":"The coiled-coil domain of PTPIP51, not its FFAT motif, is critical for binding to VAPB in cells using full-length proteins. Deletion of the coiled-coil domain abrogates PTPIP51's effects on ER-mitochondria contacts and IP3 receptor-mediated Ca2+ delivery to mitochondria.","method":"Co-immunoprecipitation of full-length deletion mutants, electron microscopy of ER-mitochondria contacts, Ca2+ imaging","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain mutagenesis with multiple orthogonal functional readouts (Co-IP, EM, Ca2+ imaging)","pmids":["36120587"],"is_preprint":false},{"year":2023,"finding":"VAPB directly interacts with IRS-1 via IRS-1's FFAT-like motif (Y745/Y746 residues). VAPB targets IRS-1 to the ER and maintains its stability. IGF-1 enhances the VAPB-IRS-1 association. VAPB ablation in mice reduces IRS-1 levels, suppresses insulin signaling, and causes glucose intolerance. The P56S mutant impairs IRS-1 ER-tethering and stability.","method":"Co-immunoprecipitation, mutagenesis of FFAT-like motif, VAPB KO mice, insulin signaling assays, glucose tolerance tests","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain mutagenesis, KO mouse phenotype, and biochemical signaling assays in one study","pmids":["37528084"],"is_preprint":false},{"year":2024,"finding":"High-speed single-molecule tracking of VAPB combined with 3D electron microscopy reveals dynamic subdomains within VAPB contact sites that correlate with ER membrane curvature. VAPB molecules enter and leave ERMCSs within seconds while the contact site itself is stable over longer timescales (metastability). The ALS-associated P56S mutation perturbs these subdomains, likely impairing ERMCS remodeling capacity.","method":"High-speed single-molecule imaging, 3D electron microscopy, VAPB-P56S mutant analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — novel structural and dynamic characterization using complementary high-resolution methods with mutant comparison","pmids":["38267577"],"is_preprint":false},{"year":2024,"finding":"Overexpression of VAPB or PTPIP51 corrects mutant TDP43-induced damage to IP3 receptor-mediated Ca2+ delivery to mitochondria and to synaptic function. Ursodeoxycholic acid (UDCA) corrects TDP43-induced disruption of the VAPB-PTPIP51 interaction by inhibiting TDP43-mediated GSK3β activation.","method":"Overexpression rescue experiments, Ca2+ imaging, synaptic electrophysiology, GSK3β activity assays, pharmacological treatment with UDCA","journal":"Acta neuropathologica communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional assays (Ca2+ imaging, electrophysiology, kinase activity) with genetic and pharmacological rescue","pmids":["38395965"],"is_preprint":false},{"year":2019,"finding":"VAPB depletion in motoneuron-like NSC34 cells increases Golgi- and acidic vesicle-localized phosphatidylinositol-4-phosphate (PI4P) and reduces neurite extension when cells are induced to differentiate. PI4K inhibitors increase neurite elongation, consistent with VAPB regulating PI4P homeostasis to support neuritogenesis.","method":"VAPB-depleted stable cell clones, PI4P immunofluorescence assay, neurite extension measurement, PI4K pharmacological inhibition","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — stable depletion clones with pharmacological rescue, single lab","pmids":["30745341"],"is_preprint":false},{"year":2022,"finding":"SNX1 endosomal tubules establish contacts with VAPB-positive ER subdomains during starvation. SNX2 (endosomal partner of SNX1) interacts with VAPB to regulate endosomal tethering to ER and promotes autophagosome biogenesis at these sites.","method":"Immunofluorescence, proximity ligation assay, co-immunoprecipitation, siRNA knockdown, live imaging","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus PLA and knockdown, single lab","pmids":["36585258"],"is_preprint":false},{"year":2014,"finding":"In a Drosophila genetic screen, TOR kinase was identified as an interactor of VAPB. TOR knockdown reversed the large bouton phenotype caused by VAP(P58S) expression in neurons. Overexpression of TSC1/2 (negative TOR regulators) or reduction of S6K also reversed VAP(P58S) phenotypes. Rapamycin (TOR inhibitor) fed to larvae reversed VAP(P58S) bouton phenotypes, indicating upregulation of TOR signaling in response to VAP(P58S).","method":"Drosophila reverse genetic screen (2635 genes), genetic epistasis, pharmacological rapamycin treatment","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in Drosophila with pharmacological validation, single lab","pmids":["25361581"],"is_preprint":false},{"year":2014,"finding":"VAP-B directly binds Rab3GAP1 (catalytic subunit of Rab3GAP) via an FFAT-like motif in Rab3GAP1. This interaction occurs even within the Rab3GAP1/2 heterodimer complex. Mutation of the FFAT-like motif reduces Rab3GAP1-VAPB binding and increases ERGIC-53 binding. Overexpression of Rab3GAP1 affects nuclear envelope formation more potently than the FFAT-motif mutant.","method":"Co-immunoprecipitation, pulldown with FFAT-like motif mutants, immunofluorescence of nuclear envelope","journal":"The Kobe journal of medical sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP with domain mutants and functional nuclear envelope assay, single lab","pmids":["25612670"],"is_preprint":false},{"year":2009,"finding":"VAP-C (a splice variant of VAP-B) interacts with NS5B but not with VAP-A, VAP-B, or NS5A. VAP-C expression inhibits NS5B interaction with VAP-A or VAP-B and impairs HCV RNA replication and propagation, acting as a negative regulator of HCV.","method":"Co-immunoprecipitation, HCV replicon assays, siRNA knockdown, overexpression in Huh-7 cells","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with competition assay and functional replication assay, single lab","pmids":["19515777"],"is_preprint":false},{"year":2017,"finding":"Secreted C. elegans VAPB homolog vMSP signals through the CLR-1 Lar-like tyrosine phosphatase receptor expressed throughout the muscle plasma membrane. MSPd signaling promotes mitochondrial reticulum remodeling in adult muscle via SMN-1, which acts in muscle colocalizing with ARX-2 (Arp2/3 component) at myofilaments.","method":"Genetic epistasis in C. elegans, RNAi suppressor screen, tissue-specific expression, co-localization imaging","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi screen plus genetic epistasis in C. elegans identifying receptor and downstream effector","pmids":["28634272"],"is_preprint":false}],"current_model":"VAPB is an ER-resident tail-anchored adaptor protein whose cytoplasm-facing MSP domain recruits FFAT-motif-containing proteins to the ER surface, thereby mediating membrane contact sites with mitochondria (via PTPIP51), peroxisomes (via ACBD5), and plasma membrane (via Kv2 channels); the VAPB-PTPIP51 tether regulates ER-to-mitochondria Ca2+ transfer, mitochondrial ATP production, autophagy, and synaptic activity, while the MSP domain is also proteolytically cleaved and secreted as a ligand for Eph receptors and Lar-like receptors on muscle, promoting Arp2/3-dependent actin remodeling and mitochondrial positioning; the ALS-linked P56S mutation misfolds the MSP domain, abolishes FFAT-binding and UPR functions, causes dominant-negative aggregation of wild-type VAPB, and is ultimately cleared by the proteasome via p97/VCP, with haploinsufficiency of the wild-type allele likely the primary driver of motor neuron degeneration."},"narrative":{"mechanistic_narrative":"VAPB is an endoplasmic reticulum (ER) tail-anchored protein that uses its cytoplasm-facing MSP domain to capture FFAT-motif-containing proteins and tether the ER to other organelles, thereby organizing membrane contact sites that control inter-organelle signaling and lipid/Ca2+ exchange [PMID:17804640, PMID:22131369]. Through this FFAT-binding activity it bridges the ER to mitochondria via PTPIP51 — a tether built primarily on the PTPIP51 coiled-coil domain — that governs ER-to-mitochondria Ca2+ transfer, mitochondrial ATP production, autophagosome formation, and synaptic function [PMID:22131369, PMID:28132811, PMID:30841933, PMID:36120587]; this tether is a convergence point disrupted by ALS/FTD- and Parkinson-associated proteins TDP-43, FUS, and α-synuclein through GSK-3β activation [PMID:24893131, PMID:27418313, PMID:28337542, PMID:38395965]. The same FFAT-recognition mechanism recruits ACBD5 to form peroxisome-ER contacts regulated by GSK3β phosphorylation [PMID:28108524, PMID:35019937], Kv2 channels to ER-plasma-membrane junctions [PMID:29941597, PMID:30012696], and adaptors such as FAF1, IRS-1, and Rab3GAP1, linking VAPB to p97-dependent protein degradation, insulin signaling, and nuclear envelope assembly [PMID:24885147, PMID:37528084, PMID:25612670]. Beyond its ER-resident adaptor role, the VAPB MSP domain is proteolytically cleaved and secreted to act as a ligand for Eph and Lar-like receptors on muscle, driving Arp2/3-dependent actin remodeling and mitochondrial positioning [PMID:18555774, PMID:22264801, PMID:28634272]. The ALS8-linked P56S mutation misfolds the MSP domain, abolishing FFAT binding and UPR function, driving co-aggregation of wild-type VAPB into organized smooth-ER inclusions that are cleared by the proteasome via p97/VCP-dependent ERAD [PMID:15372378, PMID:16891305, PMID:20008544, PMID:22611258, PMID:24252306]. VAPB also supports the unfolded protein response and ER-to-Golgi/nuclear-envelope membrane trafficking and is exploited by HCV, norovirus, HSV-1, and Chlamydia during their replication cycles [PMID:16891305, PMID:22454507, PMID:16227268, PMID:24595143, PMID:28698274, PMID:30717447].","teleology":[{"year":2004,"claim":"Established VAPB as a disease gene by linking the MSP-domain P56S mutation to dominantly inherited motor neuron disease, framing all subsequent mechanism work.","evidence":"Genetic mapping and missense mutation identification in ALS8 families","pmids":["15372378"],"confidence":"Medium","gaps":["No direct biochemical mechanism in this study","Did not define how P56S causes degeneration"]},{"year":2006,"claim":"Answered what VAPB does in ER homeostasis by showing it promotes the IRE1/XBP1 unfolded protein response and that P56S aggregates abolish this and co-aggregate wild-type protein.","evidence":"siRNA knockdown, UPR reporter assays, fractionation, and immunofluorescence","pmids":["16891305"],"confidence":"High","gaps":["Mechanism coupling VAPB to IRE1 not defined","Did not establish physiological consequence in neurons"]},{"year":2005,"claim":"Identified VAPB domain architecture for partner binding (MSP and coiled-coil) and homo/heterodimerization through the transmembrane domain, while exposing VAPB as a host factor co-opted by HCV.","evidence":"Yeast two-hybrid, Co-IP with domain mutants, siRNA, and cell-free HCV replication assay","pmids":["16227268"],"confidence":"High","gaps":["Endogenous physiological role distinct from viral hijacking not addressed"]},{"year":2007,"claim":"Defined VAPB's core molecular activity as an FFAT-motif receptor that targets lipid-binding proteins to the cytosolic ER surface, and showed P56S traps these and wild-type VAPB in immobile ER clusters.","evidence":"FRAP, Co-IP, mass spectrometry, and shRNA in primary neurons","pmids":["17804640"],"confidence":"High","gaps":["Full repertoire of FFAT clients not enumerated","Link to motor neuron death indirect"]},{"year":2008,"claim":"Revealed an unanticipated extracellular signaling role: the MSP domain is cleaved and secreted as a ligand for Eph receptors, conserved across species, and P56S blocks secretion.","evidence":"In vivo cleavage/secretion and Eph-binding assays in Drosophila and C. elegans with mutagenesis","pmids":["18555774"],"confidence":"High","gaps":["Protease responsible for cleavage not identified in mammals","Physiological relevance of secreted MSP in human motor neurons unclear"]},{"year":2008,"claim":"Mapped additional VAPB functions in membrane trafficking and transcriptional control, including ATF6 binding, nuclear envelope protein delivery, and microtubule-coupled ER-Golgi transport, all antagonized by free FFAT peptide.","evidence":"Co-IP, reporter assays, in vitro vesicle budding, microtubule co-sedimentation, and FFAT competition","pmids":["18263603","22454507","18713837"],"confidence":"Medium","gaps":["Several findings from single labs","Direct versus indirect effects on trafficking not fully resolved"]},{"year":2010,"claim":"Resolved the structural basis of P56S pathology: misfolding exposes hydrophobic patches that enhance coiled-coil-mediated oligomerization and aggregation, with the dominant-negative trapping of wild-type VAPB occurring through MSP-domain interactions.","evidence":"Mutagenesis, size-exclusion chromatography, Co-IP, yeast inositol-auxotrophy, and aggregation assays","pmids":["20207736","19183264"],"confidence":"High","gaps":["Atomic structure of the aggregate not determined","Threshold of loss-of-function versus toxic gain not quantified"]},{"year":2012,"claim":"Characterized the cellular fate of mutant VAPB, defining its inclusions as organized smooth ER cleared by p97/VCP-dependent proteasomal ERAD rather than autophagy, and showed P56S resists normal neuronal proteolytic processing.","evidence":"Cell-free translocation, EM, inducible cell lines, pulse-chase, dominant-negative p97, and developmental fractionation","pmids":["20008544","22611258","21275991"],"confidence":"High","gaps":["E3 ligase fully responsible in vivo not pinned down","Significance of regulated cleavage of wild-type VAPB unresolved"]},{"year":2011,"claim":"Discovered the VAPB-PTPIP51 ER-mitochondria tether and established its role in mitochondrial Ca2+ uptake, defining VAPB as a MAM contact-site organizer.","evidence":"Reciprocal Co-IP, MAM fractionation, mitochondria-targeted cameleon Ca2+ imaging, and siRNA","pmids":["22131369"],"confidence":"High","gaps":["Coiled-coil basis of binding clarified only later","How P56S alters tether kinetics unresolved"]},{"year":2014,"claim":"Connected the VAPB-PTPIP51 tether to neurodegeneration by showing TDP-43 disrupts it via GSK-3β, and extended VAPB tethering to peroxisomes through ACBD5.","evidence":"Co-IP, PLA, EM, Ca2+ imaging, GSK-3β modulation, and live imaging of organelle dynamics","pmids":["24893131","18555774","28108524"],"confidence":"High","gaps":["GSK-3β substrate within the tether not defined","Relative contribution of each contact site to disease unknown"]},{"year":2014,"claim":"Defined the secreted-MSP signaling axis in muscle: vMSP acts on Lar-like phosphatase and Robo receptors to drive Arp2/3-dependent actin remodeling and mitochondrial positioning, and linked VAPB to FAF1/p97, ASNA1, and Rab3GAP1 adaptors.","evidence":"Genetic epistasis in C. elegans and Drosophila, receptor binding, mitochondrial imaging, and FFAT-motif Co-IP/in vitro binding","pmids":["22264801","24885147","25612670","28634272"],"confidence":"High","gaps":["Mammalian relevance of muscle MSP signaling untested","Non-canonical FFAT-like motif consensus only partly defined"]},{"year":2017,"claim":"Generalized the VAPB-PTPIP51 tether as a regulator of autophagy and showed multiple neurodegeneration-associated proteins (FUS, α-synuclein) converge on disrupting it via GSK-3β, impairing Ca2+ transfer and ATP production.","evidence":"siRNA, overexpression, artificial-tether rescue, autophagy flux, Ca2+ imaging, ATP assays, and patient iPSC neurons","pmids":["28132811","27418313","28337542","30143980"],"confidence":"High","gaps":["Direct measurement of Ca2+ flux controlling autophagy machinery incomplete","Whether tether tightening or loosening dominates in disease unsettled"]},{"year":2018,"claim":"Expanded VAPB clients to ER-plasma-membrane junctions and ion-channel physiology, recruiting Kv2 channels via phosphorylation-dependent FFAT motifs and modulating HCN pacemaker channels with cardiac consequences.","evidence":"BioID, FRET, mass spectrometry from brain, KO cells/mice, electrophysiology, and ECG in zebrafish and mice","pmids":["29941597","30012696","29879376"],"confidence":"High","gaps":["Tissue-specific channel partner hierarchy unclear","Mechanism of HCN current enhancement not fully defined"]},{"year":2019,"claim":"Localized VAPB-PTPIP51 contacts to synapses and the inner nuclear membrane, linking the tether to synaptic activity and spine morphology and identifying nuclear-envelope proximity partners.","evidence":"PLA, synaptic electrophysiology, spine analysis, immunoEM, and APEX2-SILAC proximity proteomics","pmids":["30841933","31519755"],"confidence":"High","gaps":["INM interactors not orthogonally validated","Causal role of synaptic contacts in degeneration not established"]},{"year":2023,"claim":"Extended VAPB adaptor function to metabolic signaling by showing it tethers and stabilizes IRS-1 at the ER, with VAPB ablation suppressing insulin signaling and causing glucose intolerance.","evidence":"Co-IP, FFAT-like motif mutagenesis, VAPB KO mice, and glucose tolerance tests","pmids":["37528084"],"confidence":"High","gaps":["Relevance to ALS pathophysiology unclear","Whether P56S metabolic effects occur in patients untested"]},{"year":2024,"claim":"Resolved the nanoscale dynamics of VAPB contact sites, revealing metastable subdomains tied to membrane curvature that P56S perturbs, and validated therapeutic rescue of tether disruption.","evidence":"High-speed single-molecule tracking, 3D EM, overexpression rescue, Ca2+ imaging, electrophysiology, and UDCA treatment","pmids":["38267577","38395965"],"confidence":"High","gaps":["Molecular determinants of subdomain assembly unknown","Translation of UDCA rescue to in vivo disease not established"]},{"year":null,"claim":"How the multiple VAPB tethering functions are coordinated and prioritized in motor neurons, and whether haploinsufficiency versus toxic aggregation is the primary driver of P56S degeneration, remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Quantitative balance of loss- versus gain-of-function not resolved","Integration of contact-site, secreted-MSP, and metabolic roles in disease unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,11,18,25,34]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1,20,37]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[3,14,42]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[27,33]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,10,11,17,18]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[5,29,30]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[25,26]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[11,17]},{"term_id":"GO:0005777","term_label":"peroxisome","supporting_discovery_ids":[18,32]}],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[2,4]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[22,31,38]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[5,15,25]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,17,23]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[13,16,19]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[34,21]}],"complexes":["VAPB-PTPIP51 ER-mitochondria tether","VAPB-ACBD5 peroxisome-ER tether","VAPB-Kv2 ER-PM junction"],"partners":["PTPIP51","ACBD5","VAPA","FAF1","IRS-1","YIF1A","RAB3GAP1","SNX2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95292","full_name":"Vesicle-associated membrane protein-associated protein B/C","aliases":[],"length_aa":243,"mass_kda":27.2,"function":"Endoplasmic reticulum (ER)-anchored protein that mediates the formation of contact sites between the ER and endosomes via interaction with FFAT motif-containing proteins such as STARD3 or WDR44 (PubMed:32344433, PubMed:33124732). Interacts with STARD3 in a FFAT motif phosphorylation dependent manner (PubMed:33124732). Via interaction with WDR44 participates in neosynthesized protein export (PubMed:32344433). Participates in the endoplasmic reticulum unfolded protein response (UPR) by inducing ERN1/IRE1 activity (PubMed:16891305, PubMed:20940299). Involved in cellular calcium homeostasis regulation (PubMed:22131369)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/O95292/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/VAPB","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000124164","cell_line_id":"CID000461","localizations":[{"compartment":"er","grade":3},{"compartment":"golgi","grade":3},{"compartment":"vesicles","grade":2}],"interactors":[{"gene":"PGRMC1","stoichiometry":10.0},{"gene":"OSBP","stoichiometry":4.0},{"gene":"OSBPL11","stoichiometry":4.0},{"gene":"OSBPL9","stoichiometry":4.0},{"gene":"CANX","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"COPA","stoichiometry":0.2},{"gene":"COPB2","stoichiometry":0.2},{"gene":"COPE","stoichiometry":0.2},{"gene":"DDOST","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000461","total_profiled":1310},"omim":[{"mim_id":"619968","title":"ACYL-CoA-BINDING DOMAIN-CONTAINING PROTEIN 4; ACBD4","url":"https://www.omim.org/entry/619968"},{"mim_id":"612069","title":"AMYOTROPHIC LATERAL SCLEROSIS 10 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA; ALS10","url":"https://www.omim.org/entry/612069"},{"mim_id":"611895","title":"AMYOTROPHIC LATERAL SCLEROSIS 9; ALS9","url":"https://www.omim.org/entry/611895"},{"mim_id":"611873","title":"REGULATOR OF MICROTUBULE DYNAMICS 3; RMDN3","url":"https://www.omim.org/entry/611873"},{"mim_id":"608627","title":"AMYOTROPHIC LATERAL SCLEROSIS 8; ALS8","url":"https://www.omim.org/entry/608627"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Endoplasmic reticulum","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/VAPB"},"hgnc":{"alias_symbol":["VAP-B","VAP-C","ALS8"],"prev_symbol":[]},"alphafold":{"accession":"O95292","domains":[{"cath_id":"2.60.40.10","chopping":"8-92_118-123","consensus_level":"high","plddt":93.2736,"start":8,"end":123}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95292","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95292-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95292-F1-predicted_aligned_error_v6.png","plddt_mean":76.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VAPB","jax_strain_url":"https://www.jax.org/strain/search?query=VAPB"},"sequence":{"accession":"O95292","fasta_url":"https://rest.uniprot.org/uniprotkb/O95292.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95292/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95292"}},"corpus_meta":[{"pmid":"15372378","id":"PMC_15372378","title":"A mutation in the 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genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — genetic identification with functional inference, replicated across multiple kindreds but no direct biochemical mechanism experiment in this paper\",\n      \"pmids\": [\"15372378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"VAPB (and VAPA) interact with lipid-binding proteins carrying FFAT motifs and target them to the cytosolic surface of the ER. The P56S mutation causes aggregation of mutant VAPB in immobile tubular ER clusters, perturbs FFAT-motif binding, and traps endogenous wild-type VAPB in mutant aggregates. Reduction of VAP by shRNA in primary neurons causes Golgi dispersion and cell death.\",\n      \"method\": \"Immunofluorescence, FRAP, co-immunoprecipitation, shRNA knockdown in primary neurons, mass spectrometry\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (FRAP, Co-IP, shRNA, live imaging) establishing localization, binding, and functional consequence\",\n      \"pmids\": [\"17804640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Wild-type VAPB promotes the unfolded protein response (UPR) via the IRE1/XBP1 pathway; siRNA knockdown of VAPB attenuates UPR. The P56S mutation causes VAPB to form insoluble aggregates in non-ER fractions, abolishing its ability to mediate UPR, and the mutant protein induces co-aggregation and mislocalization of co-expressed wild-type VAPB.\",\n      \"method\": \"siRNA knockdown, overexpression, UPR reporter assays, fractionation, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (siRNA, reporter assay, fractionation) in one study establishing UPR function\",\n      \"pmids\": [\"16891305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The MSP domains of VAP proteins (VAPB/ALS8, Drosophila VAP33, C. elegans VPR-1) are cleaved and secreted as ligands for Eph receptors. The P58S mutation in Drosophila VAP33 prevents MSP domain secretion and leads to ubiquitination, ER inclusion accumulation, and an unfolded protein response.\",\n      \"method\": \"In vivo cleavage/secretion assays in Drosophila and C. elegans, Eph receptor binding assays, genetic epistasis, ubiquitination assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstitution of secretion, receptor binding, and mutagenesis across multiple model organisms\",\n      \"pmids\": [\"18555774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The MSP domain of VAPA and VAPB interacts with the ER-localized transcription factor ATF6. Overexpression of VAPB or VAPB(P56S) attenuates ATF6-regulated transcription, with the mutant being a more potent inhibitor.\",\n      \"method\": \"Co-immunoprecipitation, transcriptional reporter assays, overexpression\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus functional reporter assay, single lab\",\n      \"pmids\": [\"18263603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"VAPB function is required for transport of nucleoporins and emerin to the nuclear envelope; VAPB P56S mutation sequesters these proteins in dilated cytoplasmic ERGIC membranes. FFAT motif overexpression antagonizes mutant VAPB and restores nuclear envelope transport. Knockdown of endogenous VAPB recapitulates the nuclear envelope transport defect.\",\n      \"method\": \"Overexpression, siRNA knockdown, immunofluorescence, ERGIC marker co-localization\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional rescue and knockdown experiments, single lab, two orthogonal approaches\",\n      \"pmids\": [\"22454507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"VAPA inhibits ER-to-Golgi transport and lateral diffusion of membrane proteins via stable association with microtubules; overexpression of the FFAT motif restores transport and lateral diffusion, and disrupts VAP-microtubule association. VAPB P56S forms large ER aggregates that are resolved by FFAT overexpression.\",\n      \"method\": \"In vitro ER vesicle budding assay, live-cell imaging, microtubule co-sedimentation, FFAT peptide competition\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of vesicle budding plus live imaging and biochemical disruption assays\",\n      \"pmids\": [\"18713837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human VAPB interacts with HCV NS5A and NS5B via its MSP domain and coiled-coil domain respectively, forms homo- and heterodimers with VAPA through the transmembrane domain, co-localizes with NS5A at the ER and Golgi, and is required for HCV RNA replication; specific anti-VAPB antibody suppresses HCV RNA replication in a cell-free assay.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, mutation analysis, siRNA knockdown, cell-free replication assay, immunofluorescence\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including cell-free replication assay, Co-IP with domain mutants, and siRNA\",\n      \"pmids\": [\"16227268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"VAP-B oligomerization is primarily mediated by its coiled-coil domain; the GXXXG motif in the transmembrane domain mediates TM self-association but is insufficient for oligomerization. The P56S mutation induces conformational changes in the MSP domain exposing hydrophobic patches, which enhances oligomerization and aggregation without directly affecting FFAT binding.\",\n      \"method\": \"Mutagenesis, size-exclusion chromatography, co-immunoprecipitation, cell-based aggregation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with biochemical assays to dissect structural requirements, single lab\",\n      \"pmids\": [\"20207736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"P56S-VAPB is a loss-of-function mutant confirmed by yeast inositol-auxotrophy assay. Wild-type VAPB preferentially interacts with P56S-VAPB through the MSP domain (in addition to TM domain interactions), leading to recruitment of wild-type VAPB into cytosolic aggregates and attenuation of UPR function. P56S-VAPB expression increases vulnerability of NSC34 motoneuronal cells to ER stress-induced death.\",\n      \"method\": \"Yeast inositol-auxotrophy assay, co-immunoprecipitation, cell viability assays\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vivo yeast functional assay plus co-IP domain mapping, single lab\",\n      \"pmids\": [\"19183264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"P56S-VAPB inserts post-translationally into ER membranes identically to wild-type VAPB but rapidly clusters to form inclusions that remain continuous with the ER. Ultrastructural analysis reveals the inclusions represent a novel form of organized smooth ER (OSER) consisting of parallel cisternae interleaved by a ~30 nm electron-dense cytosolic layer.\",\n      \"method\": \"Cell-free translocation assays, confocal imaging, electron microscopy\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cell-free biochemical assay combined with ultrastructural EM analysis\",\n      \"pmids\": [\"20008544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"VAPB interacts with the outer mitochondrial membrane protein PTPIP51. VAPB is a mitochondria-associated membrane (MAM) protein. Loss of either VAPB or PTPIP51 perturbs mitochondrial Ca2+ uptake following ER store release. The P56S mutant has altered binding to PTPIP51 and increases mitochondrial Ca2+ uptake.\",\n      \"method\": \"Co-immunoprecipitation, fractionation (MAM isolation), Ca2+ imaging with mitochondria-targeted cameleon, siRNA knockdown\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, subcellular fractionation, functional Ca2+ measurements with loss-of-function\",\n      \"pmids\": [\"22131369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"VAPB undergoes proteolytic processing in neurons in a developmentally regulated manner; the C-terminal fragment remains membrane-associated with distinct localization from full-length protein. The P56S mutant is resistant to neuronal proteolysis.\",\n      \"method\": \"Western blotting in rat brain fractions during postnatal development, primary neuronal cultures, HEK293 overexpression\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — biochemical fractionation across development and cell types, single lab\",\n      \"pmids\": [\"21275991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Restructured ER generated by P56S-VAPB is cleared by the proteasome. Shortly after synthesis, mutant VAPB forms small polyubiquitinated clusters that congregate in the juxtanuclear region. Clearance involves p97/VCP ATPase activity (dominant-negative p97 stabilizes mutant VAPB). Clearance does not involve macro-autophagy.\",\n      \"method\": \"Stable inducible cell lines (Tet-Off), proteasome inhibitors, autophagy inhibitors, dominant-negative p97, pulse-chase, microinjection\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal pharmacological and genetic approaches in inducible system\",\n      \"pmids\": [\"22611258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"VAPB secreted MSP domain (vMSP) acts on Lar-like protein-tyrosine phosphatase and Roundabout (Robo) growth cone guidance receptors on striated muscle, promoting Arp2/3-dependent actin remodeling and mitochondrial localization to actin-rich muscle I-bands. VAPB mutants have mitochondrial localization, morphology, mobility, and fission/fusion defects suppressible by Lar-like receptor or Arp2/3 inactivation.\",\n      \"method\": \"Genetic epistasis in C. elegans and Drosophila, receptor binding assays, mitochondrial imaging, actin remodeling assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in two model organisms with receptor binding and cellular phenotype rescue\",\n      \"pmids\": [\"22264801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"VAPB interacts with YIF1A (an ER-Golgi recycling protein) via transmembrane regions. VAPB is required for intracellular membrane trafficking into dendrites and normal dendritic morphology. P56S-VAPB recruits YIF1A into ER clusters, displacing it from ERGIC compartments.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid, immunofluorescence in hippocampal neurons, siRNA knockdown\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus neuronal localization and functional knockdown\",\n      \"pmids\": [\"23736259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"VAPB-P56S inclusions in transgenic mouse motor neurons are immunoreactive for ERAD pathway factors (p97/VCP, Derlin-1, BAP31) and represent a reversible ER quality control compartment. Proteasome inhibition increases inclusion size; knockdown of TEB4 (ERAD E3 ligase) reduces inclusion size; BAP31 knockdown increases inclusion size.\",\n      \"method\": \"Immunohistochemistry, transgenic mouse model, siRNA knockdown, proteasome inhibition in primary neuron cultures\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological manipulation with defined inclusion phenotypes, single lab\",\n      \"pmids\": [\"24252306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"VAPB interacts with the mitochondrial protein PTPIP51 to tether ER to mitochondria. TDP-43 perturbs ER-mitochondria interactions by disrupting the VAPB-PTPIP51 interaction via activation of GSK-3β. Disrupted VAPB-PTPIP51 interaction is accompanied by altered cellular Ca2+ homeostasis.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, electron microscopy, Ca2+ measurements, GSK-3β inhibitors/activators, siRNA knockdown\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including EM, PLA, Ca2+ imaging, pharmacological and genetic modulation\",\n      \"pmids\": [\"24893131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"VAPB interacts with the peroxisomal membrane protein ACBD5 to mediate peroxisome-ER associations. Loss of this interaction perturbs peroxisome membrane expansion and increases peroxisome movement.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, electron microscopy, live imaging of peroxisome dynamics, siRNA knockdown\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, EM, live imaging, and functional loss-of-function in one study\",\n      \"pmids\": [\"28108524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"VAPB interacts with FAF1 (a p97 ATPase cofactor) via a non-canonical FFAT-like motif in FAF1, thereby linking VAPB to p97 function. VAPB also interacts with ASNA1 (TRC complex subunit) via a similar FFAT-like motif. Proteasome inhibition increases ubiquitinated species in VAPB immunoprecipitates and increases FAF1/p97 binding. FAF1 siRNA reduces VAPB interaction with ubiquitinated proteins.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assays with recombinant proteins, siRNA knockdown, FFAT motif mutagenesis\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro binding with recombinant proteins plus cellular Co-IP and siRNA validation\",\n      \"pmids\": [\"24885147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Expression of the C. trachomatis effector IncD on the inclusion membrane causes massive recruitment of CERT lipid transfer protein via its PH domain, which in turn recruits VAPB to the inclusion; the CERT-VAPB interaction at the inclusion relies on the FFAT domain of CERT.\",\n      \"method\": \"Conditional IncD expression in C. trachomatis, immunofluorescence, domain deletion analysis\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic conditional expression system plus domain-specific mutants, single lab\",\n      \"pmids\": [\"24595143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ALS/FTD-associated mutant FUS disrupts the VAPB-PTPIP51 interaction and ER-mitochondria associations via activation of GSK-3β, impairing mitochondrial Ca2+ uptake and ATP production.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, Ca2+ imaging, ATP assays, GSK-3β inhibitors\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, PLA, Ca2+ imaging, ATP measurement) in one study\",\n      \"pmids\": [\"27418313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The VAPB-PTPIP51 ER-mitochondria tethers regulate autophagy: overexpression of VAPB or PTPIP51 (tightening contacts) impairs autophagosome formation, while siRNA loss stimulates it. An artificial ER-mitochondria linker rescues the effects of VAPB/PTPIP51 siRNA, confirming the tethering function mediates the autophagic regulation. The mechanism involves VAPB-PTPIP51-mediated delivery of Ca2+ to mitochondria.\",\n      \"method\": \"siRNA knockdown, overexpression, artificial tether rescue, autophagy flux assays, Ca2+ imaging\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — orthogonal genetic approaches including artificial tether rescue, Ca2+ imaging, and autophagy flux measurement\",\n      \"pmids\": [\"28132811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"α-Synuclein binds directly to VAPB, and overexpression of wild-type or familial PD mutant α-synuclein disrupts the VAPB-PTPIP51 tethers, loosening ER-mitochondria associations and disrupting Ca2+ exchange and mitochondrial ATP production.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, Ca2+ imaging, mitochondrial ATP measurements, iPSC-derived neurons from PD patients\",\n      \"journal\": \"Acta neuropathologica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, PLA, Ca2+ imaging, ATP assay, and patient iPSC-derived neuron validation\",\n      \"pmids\": [\"28337542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Murine norovirus requires VAPA and VAPB for replication; viral NS1/2 protein contains an FFAT motif mimic that binds the MSP domain of VAPA/VAPB. Mutations in NS1 disrupting VAPB/VAPA interaction inhibit viral replication.\",\n      \"method\": \"Genetic deletion of VAPA/VAPB, structural analysis (FFAT mimic identification), mutagenesis, viral replication assays\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — genetic KO plus structural analysis and mutagenesis of binding interface, single lab\",\n      \"pmids\": [\"28698274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Kv2.1 and Kv2.2 voltage-gated K+ channels interact with VAPA and VAPB at ER-PM junctions via a non-canonical phosphorylation-dependent FFAT motif in the Kv2 C-terminus. VAP binding recruits Kv2 channels to ER-PM contact sites. VAPA knockout reduces Kv2.1 clustering.\",\n      \"method\": \"Proximity-based biotinylation (BioID), FRET, siRNA knockdown, colocalization assays, CD4-chimera domain mapping, KO cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (BioID, FRET, siRNA, KO, domain mapping) in one study\",\n      \"pmids\": [\"29941597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"VAPB (and VAPA) are identified as prominent Kv2.1-associated proteins in brain; VAPs are recruited to ER-PM junctions by Kv2.1 or Kv2.2 expression. The VAPB-Kv2 association relies on the FFAT-binding domain on VAPA/VAPB and a non-canonical phosphorylation-dependent FFAT motif (PRC/clustering domain) on Kv2. VAPA knockout reduces Kv2.1 clustering in mammalian cells.\",\n      \"method\": \"Affinity immunopurification + mass spectrometry from brain, Kv2.1 KO mice, VAPA KO cells, multiplex immunolabeling in brain sections\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mass spectrometry from brain tissue, KO validation, in situ co-localization in neurons\",\n      \"pmids\": [\"30012696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"VAPB is an essential modulator of HCN1 and HCN2 pacemaker channels; VAPB significantly increases HCN2 currents and surface expression and influences dendritic distribution of HCN2 in neurons. VAPB-deficient zebrafish and VAPB-/- mice exhibit cardiac bradycardia, demonstrating a physiological role for VAPB in cardiac pacemaker function.\",\n      \"method\": \"Electrophysiology (patch clamp), surface expression assays, VAPB KO zebrafish and mice, ECG recordings\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — electrophysiology plus KO animal models in two species with defined physiological phenotypes\",\n      \"pmids\": [\"29879376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VAPB and PTPIP51 localize to and form contacts at synapses. Stimulating neuronal activity increases ER-mitochondria contacts and VAPB-PTPIP51 interaction. siRNA loss of VAPB or PTPIP51 perturbs synaptic activity and dendritic spine morphology.\",\n      \"method\": \"Immunofluorescence, proximity ligation assay, synaptic electrophysiology, siRNA knockdown, spine morphology analysis\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — PLA, electrophysiology, and morphological analysis with genetic loss-of-function\",\n      \"pmids\": [\"30841933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VAPB localizes to the inner nuclear membrane (INM) as demonstrated by immunoelectron microscopy. Proximity proteomics (APEX2-SILAC targeted to VAPB) identified emerin, TMEM43, and ELYS as potential VAPB interaction partners at the INM and nuclear pore complex.\",\n      \"method\": \"Immunoelectron microscopy, rapamycin-dependent APEX2 proximity labeling, SILAC mass spectrometry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — immunoEM plus proximity proteomics, single lab; interactions not confirmed by orthogonal methods\",\n      \"pmids\": [\"31519755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VAPB facilitates nuclear egress of HSV-1; a subpopulation of VAPB is present in the nuclear membrane co-localizing with viral pUL34. VAPB knockdown significantly reduces both cell-associated and supernatant virus titers and reduces cytoplasmic accumulation of virus particles while increasing nuclear encapsidated viral DNA. Immunogold-EM confirms VAPB associated with primary enveloped HSV-1 particles.\",\n      \"method\": \"siRNA knockdown, viral titer assays, immunofluorescence, immunogold electron microscopy\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA plus immunoEM showing VAPB with virions, single lab\",\n      \"pmids\": [\"30717447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss of VAPB induces upregulation of beclin 1 at the transcriptional level, promoting LC3 conversion, autophagosome formation, and autophagic flux including degradation of p62 and neurodegenerative disease proteins. VAPB overexpression inhibits these processes.\",\n      \"method\": \"siRNA knockdown, overexpression, Western blot for autophagy markers (LC3, p62, beclin 1), autophagic flux assays\",\n      \"journal\": \"Neuroscience bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — genetic gain- and loss-of-function with multiple autophagy markers, single lab\",\n      \"pmids\": [\"30143980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Peroxisome-ER associations via the ACBD5-VAPB tether are regulated by phosphorylation of the FFAT-like motif of ACBD5. GSK3β regulates ACBD5-VAPB binding and thus peroxisome-ER contact sites. Phosphorylation sites in the flanking regions and core of the FFAT-like motif differentially alter VAPB interaction.\",\n      \"method\": \"Co-immunoprecipitation, phosphatase treatment, site-directed mutagenesis of phosphorylation sites, GSK3β inhibitors/activators, proximity ligation assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis of phosphorylation sites, kinase manipulation, and multiple binding assays in one study\",\n      \"pmids\": [\"35019937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The coiled-coil domain of PTPIP51, not its FFAT motif, is critical for binding to VAPB in cells using full-length proteins. Deletion of the coiled-coil domain abrogates PTPIP51's effects on ER-mitochondria contacts and IP3 receptor-mediated Ca2+ delivery to mitochondria.\",\n      \"method\": \"Co-immunoprecipitation of full-length deletion mutants, electron microscopy of ER-mitochondria contacts, Ca2+ imaging\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain mutagenesis with multiple orthogonal functional readouts (Co-IP, EM, Ca2+ imaging)\",\n      \"pmids\": [\"36120587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VAPB directly interacts with IRS-1 via IRS-1's FFAT-like motif (Y745/Y746 residues). VAPB targets IRS-1 to the ER and maintains its stability. IGF-1 enhances the VAPB-IRS-1 association. VAPB ablation in mice reduces IRS-1 levels, suppresses insulin signaling, and causes glucose intolerance. The P56S mutant impairs IRS-1 ER-tethering and stability.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis of FFAT-like motif, VAPB KO mice, insulin signaling assays, glucose tolerance tests\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain mutagenesis, KO mouse phenotype, and biochemical signaling assays in one study\",\n      \"pmids\": [\"37528084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"High-speed single-molecule tracking of VAPB combined with 3D electron microscopy reveals dynamic subdomains within VAPB contact sites that correlate with ER membrane curvature. VAPB molecules enter and leave ERMCSs within seconds while the contact site itself is stable over longer timescales (metastability). The ALS-associated P56S mutation perturbs these subdomains, likely impairing ERMCS remodeling capacity.\",\n      \"method\": \"High-speed single-molecule imaging, 3D electron microscopy, VAPB-P56S mutant analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — novel structural and dynamic characterization using complementary high-resolution methods with mutant comparison\",\n      \"pmids\": [\"38267577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Overexpression of VAPB or PTPIP51 corrects mutant TDP43-induced damage to IP3 receptor-mediated Ca2+ delivery to mitochondria and to synaptic function. Ursodeoxycholic acid (UDCA) corrects TDP43-induced disruption of the VAPB-PTPIP51 interaction by inhibiting TDP43-mediated GSK3β activation.\",\n      \"method\": \"Overexpression rescue experiments, Ca2+ imaging, synaptic electrophysiology, GSK3β activity assays, pharmacological treatment with UDCA\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional assays (Ca2+ imaging, electrophysiology, kinase activity) with genetic and pharmacological rescue\",\n      \"pmids\": [\"38395965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VAPB depletion in motoneuron-like NSC34 cells increases Golgi- and acidic vesicle-localized phosphatidylinositol-4-phosphate (PI4P) and reduces neurite extension when cells are induced to differentiate. PI4K inhibitors increase neurite elongation, consistent with VAPB regulating PI4P homeostasis to support neuritogenesis.\",\n      \"method\": \"VAPB-depleted stable cell clones, PI4P immunofluorescence assay, neurite extension measurement, PI4K pharmacological inhibition\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — stable depletion clones with pharmacological rescue, single lab\",\n      \"pmids\": [\"30745341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SNX1 endosomal tubules establish contacts with VAPB-positive ER subdomains during starvation. SNX2 (endosomal partner of SNX1) interacts with VAPB to regulate endosomal tethering to ER and promotes autophagosome biogenesis at these sites.\",\n      \"method\": \"Immunofluorescence, proximity ligation assay, co-immunoprecipitation, siRNA knockdown, live imaging\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus PLA and knockdown, single lab\",\n      \"pmids\": [\"36585258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In a Drosophila genetic screen, TOR kinase was identified as an interactor of VAPB. TOR knockdown reversed the large bouton phenotype caused by VAP(P58S) expression in neurons. Overexpression of TSC1/2 (negative TOR regulators) or reduction of S6K also reversed VAP(P58S) phenotypes. Rapamycin (TOR inhibitor) fed to larvae reversed VAP(P58S) bouton phenotypes, indicating upregulation of TOR signaling in response to VAP(P58S).\",\n      \"method\": \"Drosophila reverse genetic screen (2635 genes), genetic epistasis, pharmacological rapamycin treatment\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in Drosophila with pharmacological validation, single lab\",\n      \"pmids\": [\"25361581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"VAP-B directly binds Rab3GAP1 (catalytic subunit of Rab3GAP) via an FFAT-like motif in Rab3GAP1. This interaction occurs even within the Rab3GAP1/2 heterodimer complex. Mutation of the FFAT-like motif reduces Rab3GAP1-VAPB binding and increases ERGIC-53 binding. Overexpression of Rab3GAP1 affects nuclear envelope formation more potently than the FFAT-motif mutant.\",\n      \"method\": \"Co-immunoprecipitation, pulldown with FFAT-like motif mutants, immunofluorescence of nuclear envelope\",\n      \"journal\": \"The Kobe journal of medical sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP with domain mutants and functional nuclear envelope assay, single lab\",\n      \"pmids\": [\"25612670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"VAP-C (a splice variant of VAP-B) interacts with NS5B but not with VAP-A, VAP-B, or NS5A. VAP-C expression inhibits NS5B interaction with VAP-A or VAP-B and impairs HCV RNA replication and propagation, acting as a negative regulator of HCV.\",\n      \"method\": \"Co-immunoprecipitation, HCV replicon assays, siRNA knockdown, overexpression in Huh-7 cells\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with competition assay and functional replication assay, single lab\",\n      \"pmids\": [\"19515777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Secreted C. elegans VAPB homolog vMSP signals through the CLR-1 Lar-like tyrosine phosphatase receptor expressed throughout the muscle plasma membrane. MSPd signaling promotes mitochondrial reticulum remodeling in adult muscle via SMN-1, which acts in muscle colocalizing with ARX-2 (Arp2/3 component) at myofilaments.\",\n      \"method\": \"Genetic epistasis in C. elegans, RNAi suppressor screen, tissue-specific expression, co-localization imaging\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi screen plus genetic epistasis in C. elegans identifying receptor and downstream effector\",\n      \"pmids\": [\"28634272\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VAPB is an ER-resident tail-anchored adaptor protein whose cytoplasm-facing MSP domain recruits FFAT-motif-containing proteins to the ER surface, thereby mediating membrane contact sites with mitochondria (via PTPIP51), peroxisomes (via ACBD5), and plasma membrane (via Kv2 channels); the VAPB-PTPIP51 tether regulates ER-to-mitochondria Ca2+ transfer, mitochondrial ATP production, autophagy, and synaptic activity, while the MSP domain is also proteolytically cleaved and secreted as a ligand for Eph receptors and Lar-like receptors on muscle, promoting Arp2/3-dependent actin remodeling and mitochondrial positioning; the ALS-linked P56S mutation misfolds the MSP domain, abolishes FFAT-binding and UPR functions, causes dominant-negative aggregation of wild-type VAPB, and is ultimately cleared by the proteasome via p97/VCP, with haploinsufficiency of the wild-type allele likely the primary driver of motor neuron degeneration.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"VAPB is an endoplasmic reticulum (ER) tail-anchored protein that uses its cytoplasm-facing MSP domain to capture FFAT-motif-containing proteins and tether the ER to other organelles, thereby organizing membrane contact sites that control inter-organelle signaling and lipid/Ca2+ exchange [#1, #11]. Through this FFAT-binding activity it bridges the ER to mitochondria via PTPIP51 — a tether built primarily on the PTPIP51 coiled-coil domain — that governs ER-to-mitochondria Ca2+ transfer, mitochondrial ATP production, autophagosome formation, and synaptic function [#11, #22, #28, #33]; this tether is a convergence point disrupted by ALS/FTD- and Parkinson-associated proteins TDP-43, FUS, and α-synuclein through GSK-3β activation [#17, #21, #23, #36]. The same FFAT-recognition mechanism recruits ACBD5 to form peroxisome-ER contacts regulated by GSK3β phosphorylation [#18, #32], Kv2 channels to ER-plasma-membrane junctions [#25, #26], and adaptors such as FAF1, IRS-1, and Rab3GAP1, linking VAPB to p97-dependent protein degradation, insulin signaling, and nuclear envelope assembly [#19, #34, #40]. Beyond its ER-resident adaptor role, the VAPB MSP domain is proteolytically cleaved and secreted to act as a ligand for Eph and Lar-like receptors on muscle, driving Arp2/3-dependent actin remodeling and mitochondrial positioning [#3, #14, #42]. The ALS8-linked P56S mutation misfolds the MSP domain, abolishing FFAT binding and UPR function, driving co-aggregation of wild-type VAPB into organized smooth-ER inclusions that are cleared by the proteasome via p97/VCP-dependent ERAD [#0, #2, #10, #13, #16]. VAPB also supports the unfolded protein response and ER-to-Golgi/nuclear-envelope membrane trafficking and is exploited by HCV, norovirus, HSV-1, and Chlamydia during their replication cycles [#2, #5, #7, #20, #24, #30].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established VAPB as a disease gene by linking the MSP-domain P56S mutation to dominantly inherited motor neuron disease, framing all subsequent mechanism work.\",\n      \"evidence\": \"Genetic mapping and missense mutation identification in ALS8 families\",\n      \"pmids\": [\"15372378\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct biochemical mechanism in this study\", \"Did not define how P56S causes degeneration\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Answered what VAPB does in ER homeostasis by showing it promotes the IRE1/XBP1 unfolded protein response and that P56S aggregates abolish this and co-aggregate wild-type protein.\",\n      \"evidence\": \"siRNA knockdown, UPR reporter assays, fractionation, and immunofluorescence\",\n      \"pmids\": [\"16891305\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling VAPB to IRE1 not defined\", \"Did not establish physiological consequence in neurons\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified VAPB domain architecture for partner binding (MSP and coiled-coil) and homo/heterodimerization through the transmembrane domain, while exposing VAPB as a host factor co-opted by HCV.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP with domain mutants, siRNA, and cell-free HCV replication assay\",\n      \"pmids\": [\"16227268\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous physiological role distinct from viral hijacking not addressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined VAPB's core molecular activity as an FFAT-motif receptor that targets lipid-binding proteins to the cytosolic ER surface, and showed P56S traps these and wild-type VAPB in immobile ER clusters.\",\n      \"evidence\": \"FRAP, Co-IP, mass spectrometry, and shRNA in primary neurons\",\n      \"pmids\": [\"17804640\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full repertoire of FFAT clients not enumerated\", \"Link to motor neuron death indirect\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed an unanticipated extracellular signaling role: the MSP domain is cleaved and secreted as a ligand for Eph receptors, conserved across species, and P56S blocks secretion.\",\n      \"evidence\": \"In vivo cleavage/secretion and Eph-binding assays in Drosophila and C. elegans with mutagenesis\",\n      \"pmids\": [\"18555774\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protease responsible for cleavage not identified in mammals\", \"Physiological relevance of secreted MSP in human motor neurons unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapped additional VAPB functions in membrane trafficking and transcriptional control, including ATF6 binding, nuclear envelope protein delivery, and microtubule-coupled ER-Golgi transport, all antagonized by free FFAT peptide.\",\n      \"evidence\": \"Co-IP, reporter assays, in vitro vesicle budding, microtubule co-sedimentation, and FFAT competition\",\n      \"pmids\": [\"18263603\", \"22454507\", \"18713837\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Several findings from single labs\", \"Direct versus indirect effects on trafficking not fully resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved the structural basis of P56S pathology: misfolding exposes hydrophobic patches that enhance coiled-coil-mediated oligomerization and aggregation, with the dominant-negative trapping of wild-type VAPB occurring through MSP-domain interactions.\",\n      \"evidence\": \"Mutagenesis, size-exclusion chromatography, Co-IP, yeast inositol-auxotrophy, and aggregation assays\",\n      \"pmids\": [\"20207736\", \"19183264\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic structure of the aggregate not determined\", \"Threshold of loss-of-function versus toxic gain not quantified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Characterized the cellular fate of mutant VAPB, defining its inclusions as organized smooth ER cleared by p97/VCP-dependent proteasomal ERAD rather than autophagy, and showed P56S resists normal neuronal proteolytic processing.\",\n      \"evidence\": \"Cell-free translocation, EM, inducible cell lines, pulse-chase, dominant-negative p97, and developmental fractionation\",\n      \"pmids\": [\"20008544\", \"22611258\", \"21275991\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase fully responsible in vivo not pinned down\", \"Significance of regulated cleavage of wild-type VAPB unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovered the VAPB-PTPIP51 ER-mitochondria tether and established its role in mitochondrial Ca2+ uptake, defining VAPB as a MAM contact-site organizer.\",\n      \"evidence\": \"Reciprocal Co-IP, MAM fractionation, mitochondria-targeted cameleon Ca2+ imaging, and siRNA\",\n      \"pmids\": [\"22131369\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coiled-coil basis of binding clarified only later\", \"How P56S alters tether kinetics unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected the VAPB-PTPIP51 tether to neurodegeneration by showing TDP-43 disrupts it via GSK-3β, and extended VAPB tethering to peroxisomes through ACBD5.\",\n      \"evidence\": \"Co-IP, PLA, EM, Ca2+ imaging, GSK-3β modulation, and live imaging of organelle dynamics\",\n      \"pmids\": [\"24893131\", \"18555774\", \"28108524\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"GSK-3β substrate within the tether not defined\", \"Relative contribution of each contact site to disease unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the secreted-MSP signaling axis in muscle: vMSP acts on Lar-like phosphatase and Robo receptors to drive Arp2/3-dependent actin remodeling and mitochondrial positioning, and linked VAPB to FAF1/p97, ASNA1, and Rab3GAP1 adaptors.\",\n      \"evidence\": \"Genetic epistasis in C. elegans and Drosophila, receptor binding, mitochondrial imaging, and FFAT-motif Co-IP/in vitro binding\",\n      \"pmids\": [\"22264801\", \"24885147\", \"25612670\", \"28634272\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian relevance of muscle MSP signaling untested\", \"Non-canonical FFAT-like motif consensus only partly defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Generalized the VAPB-PTPIP51 tether as a regulator of autophagy and showed multiple neurodegeneration-associated proteins (FUS, α-synuclein) converge on disrupting it via GSK-3β, impairing Ca2+ transfer and ATP production.\",\n      \"evidence\": \"siRNA, overexpression, artificial-tether rescue, autophagy flux, Ca2+ imaging, ATP assays, and patient iPSC neurons\",\n      \"pmids\": [\"28132811\", \"27418313\", \"28337542\", \"30143980\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct measurement of Ca2+ flux controlling autophagy machinery incomplete\", \"Whether tether tightening or loosening dominates in disease unsettled\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Expanded VAPB clients to ER-plasma-membrane junctions and ion-channel physiology, recruiting Kv2 channels via phosphorylation-dependent FFAT motifs and modulating HCN pacemaker channels with cardiac consequences.\",\n      \"evidence\": \"BioID, FRET, mass spectrometry from brain, KO cells/mice, electrophysiology, and ECG in zebrafish and mice\",\n      \"pmids\": [\"29941597\", \"30012696\", \"29879376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific channel partner hierarchy unclear\", \"Mechanism of HCN current enhancement not fully defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Localized VAPB-PTPIP51 contacts to synapses and the inner nuclear membrane, linking the tether to synaptic activity and spine morphology and identifying nuclear-envelope proximity partners.\",\n      \"evidence\": \"PLA, synaptic electrophysiology, spine analysis, immunoEM, and APEX2-SILAC proximity proteomics\",\n      \"pmids\": [\"30841933\", \"31519755\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"INM interactors not orthogonally validated\", \"Causal role of synaptic contacts in degeneration not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended VAPB adaptor function to metabolic signaling by showing it tethers and stabilizes IRS-1 at the ER, with VAPB ablation suppressing insulin signaling and causing glucose intolerance.\",\n      \"evidence\": \"Co-IP, FFAT-like motif mutagenesis, VAPB KO mice, and glucose tolerance tests\",\n      \"pmids\": [\"37528084\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relevance to ALS pathophysiology unclear\", \"Whether P56S metabolic effects occur in patients untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the nanoscale dynamics of VAPB contact sites, revealing metastable subdomains tied to membrane curvature that P56S perturbs, and validated therapeutic rescue of tether disruption.\",\n      \"evidence\": \"High-speed single-molecule tracking, 3D EM, overexpression rescue, Ca2+ imaging, electrophysiology, and UDCA treatment\",\n      \"pmids\": [\"38267577\", \"38395965\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular determinants of subdomain assembly unknown\", \"Translation of UDCA rescue to in vivo disease not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple VAPB tethering functions are coordinated and prioritized in motor neurons, and whether haploinsufficiency versus toxic aggregation is the primary driver of P56S degeneration, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative balance of loss- versus gain-of-function not resolved\", \"Integration of contact-site, secreted-MSP, and metabolic roles in disease unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 11, 18, 25, 34]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1, 20, 37]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [3, 14, 42]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [27, 33]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 10, 11, 17, 18]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [5, 29, 30]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [25, 26]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [11, 17]},\n      {\"term_id\": \"GO:0005777\", \"supporting_discovery_ids\": [18, 32]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [22, 31, 38]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [5, 15, 25]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 17, 23]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [13, 16, 19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [34, 21]}\n    ],\n    \"complexes\": [\n      \"VAPB-PTPIP51 ER-mitochondria tether\",\n      \"VAPB-ACBD5 peroxisome-ER tether\",\n      \"VAPB-Kv2 ER-PM junction\"\n    ],\n    \"partners\": [\n      \"PTPIP51\",\n      \"ACBD5\",\n      \"VAPA\",\n      \"FAF1\",\n      \"IRS-1\",\n      \"YIF1A\",\n      \"Rab3GAP1\",\n      \"SNX2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}