Affinage

VAPB

Vesicle-associated membrane protein-associated protein B/C · UniProt O95292

Length
243 aa
Mass
27.2 kDa
Annotated
2026-06-11
100 papers in source corpus 43 papers cited in narrative 43 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2004 Medium

    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

    PMID:15372378

    Open questions at the time
    • No direct biochemical mechanism in this study
    • Did not define how P56S causes degeneration
  2. 2006 High

    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

    PMID:16891305

    Open questions at the time
    • Mechanism coupling VAPB to IRE1 not defined
    • Did not establish physiological consequence in neurons
  3. 2005 High

    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

    PMID:16227268

    Open questions at the time
    • Endogenous physiological role distinct from viral hijacking not addressed
  4. 2007 High

    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

    PMID:17804640

    Open questions at the time
    • Full repertoire of FFAT clients not enumerated
    • Link to motor neuron death indirect
  5. 2008 High

    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

    PMID:18555774

    Open questions at the time
    • Protease responsible for cleavage not identified in mammals
    • Physiological relevance of secreted MSP in human motor neurons unclear
  6. 2008 Medium

    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

    PMID:18263603 PMID:18713837 PMID:22454507

    Open questions at the time
    • Several findings from single labs
    • Direct versus indirect effects on trafficking not fully resolved
  7. 2010 High

    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

    PMID:19183264 PMID:20207736

    Open questions at the time
    • Atomic structure of the aggregate not determined
    • Threshold of loss-of-function versus toxic gain not quantified
  8. 2012 High

    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

    PMID:20008544 PMID:21275991 PMID:22611258

    Open questions at the time
    • E3 ligase fully responsible in vivo not pinned down
    • Significance of regulated cleavage of wild-type VAPB unresolved
  9. 2011 High

    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

    PMID:22131369

    Open questions at the time
    • Coiled-coil basis of binding clarified only later
    • How P56S alters tether kinetics unresolved
  10. 2014 High

    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

    PMID:18555774 PMID:24893131 PMID:28108524

    Open questions at the time
    • GSK-3β substrate within the tether not defined
    • Relative contribution of each contact site to disease unknown
  11. 2014 High

    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

    PMID:22264801 PMID:24885147 PMID:25612670 PMID:28634272

    Open questions at the time
    • Mammalian relevance of muscle MSP signaling untested
    • Non-canonical FFAT-like motif consensus only partly defined
  12. 2017 High

    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

    PMID:27418313 PMID:28132811 PMID:28337542 PMID:30143980

    Open questions at the time
    • Direct measurement of Ca2+ flux controlling autophagy machinery incomplete
    • Whether tether tightening or loosening dominates in disease unsettled
  13. 2018 High

    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

    PMID:29879376 PMID:29941597 PMID:30012696

    Open questions at the time
    • Tissue-specific channel partner hierarchy unclear
    • Mechanism of HCN current enhancement not fully defined
  14. 2019 High

    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

    PMID:30841933 PMID:31519755

    Open questions at the time
    • INM interactors not orthogonally validated
    • Causal role of synaptic contacts in degeneration not established
  15. 2023 High

    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

    PMID:37528084

    Open questions at the time
    • Relevance to ALS pathophysiology unclear
    • Whether P56S metabolic effects occur in patients untested
  16. 2024 High

    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

    PMID:38267577 PMID:38395965

    Open questions at the time
    • Molecular determinants of subdomain assembly unknown
    • Translation of UDCA rescue to in vivo disease not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • Quantitative balance of loss- versus gain-of-function not resolved
  • Integration of contact-site, secreted-MSP, and metabolic roles in disease unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0008289 lipid binding 3 GO:0048018 receptor ligand activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005783 endoplasmic reticulum 5 GO:0005635 nuclear envelope 3 GO:0005739 mitochondrion 2 GO:0005777 peroxisome 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-9609507 Protein localization 3 R-HSA-9612973 Autophagy 3 R-HSA-162582 Signal Transduction 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
ACBD5FAF1IRS-1PTPIP51RAB3GAP1SNX2VAPAYIF1A
Complex memberships
VAPB-ACBD5 peroxisome-ER tetherVAPB-Kv2 ER-PM junctionVAPB-PTPIP51 ER-mitochondria tether

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 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. Genetic mapping, missense mutation identification, haplotype analysis in affected families American journal of human genetics Medium 15372378
2007 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. Immunofluorescence, FRAP, co-immunoprecipitation, shRNA knockdown in primary neurons, mass spectrometry The Journal of neuroscience High 17804640
2006 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. siRNA knockdown, overexpression, UPR reporter assays, fractionation, immunofluorescence The Journal of biological chemistry High 16891305
2008 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. In vivo cleavage/secretion assays in Drosophila and C. elegans, Eph receptor binding assays, genetic epistasis, ubiquitination assays Cell High 18555774
2008 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. Co-immunoprecipitation, transcriptional reporter assays, overexpression Human molecular genetics Medium 18263603
2008 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. Overexpression, siRNA knockdown, immunofluorescence, ERGIC marker co-localization Journal of cell science Medium 22454507
2008 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. In vitro ER vesicle budding assay, live-cell imaging, microtubule co-sedimentation, FFAT peptide competition Journal of cell science High 18713837
2005 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. Yeast two-hybrid, co-immunoprecipitation, mutation analysis, siRNA knockdown, cell-free replication assay, immunofluorescence Journal of virology High 16227268
2010 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. Mutagenesis, size-exclusion chromatography, co-immunoprecipitation, cell-based aggregation assays The Journal of biological chemistry High 20207736
2009 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. Yeast inositol-auxotrophy assay, co-immunoprecipitation, cell viability assays Journal of neurochemistry High 19183264
2009 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. Cell-free translocation assays, confocal imaging, electron microscopy FASEB journal High 20008544
2011 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. Co-immunoprecipitation, fractionation (MAM isolation), Ca2+ imaging with mitochondria-targeted cameleon, siRNA knockdown Human molecular genetics High 22131369
2011 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. Western blotting in rat brain fractions during postnatal development, primary neuronal cultures, HEK293 overexpression Journal of neurochemistry Medium 21275991
2012 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. Stable inducible cell lines (Tet-Off), proteasome inhibitors, autophagy inhibitors, dominant-negative p97, pulse-chase, microinjection Journal of cell science High 22611258
2012 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. Genetic epistasis in C. elegans and Drosophila, receptor binding assays, mitochondrial imaging, actin remodeling assays Developmental cell High 22264801
2013 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. Co-immunoprecipitation, yeast two-hybrid, immunofluorescence in hippocampal neurons, siRNA knockdown The EMBO journal High 23736259
2013 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. Immunohistochemistry, transgenic mouse model, siRNA knockdown, proteasome inhibition in primary neuron cultures Acta neuropathologica communications Medium 24252306
2014 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. Co-immunoprecipitation, proximity ligation assay, electron microscopy, Ca2+ measurements, GSK-3β inhibitors/activators, siRNA knockdown Nature communications High 24893131
2014 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. Co-immunoprecipitation, proximity ligation assay, electron microscopy, live imaging of peroxisome dynamics, siRNA knockdown The Journal of cell biology High 28108524
2014 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. Co-immunoprecipitation, in vitro binding assays with recombinant proteins, siRNA knockdown, FFAT motif mutagenesis BMC biology High 24885147
2014 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. Conditional IncD expression in C. trachomatis, immunofluorescence, domain deletion analysis Infection and immunity Medium 24595143
2016 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. Co-immunoprecipitation, proximity ligation assay, Ca2+ imaging, ATP assays, GSK-3β inhibitors EMBO reports High 27418313
2017 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. siRNA knockdown, overexpression, artificial tether rescue, autophagy flux assays, Ca2+ imaging Current biology High 28132811
2017 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. Co-immunoprecipitation, proximity ligation assay, Ca2+ imaging, mitochondrial ATP measurements, iPSC-derived neurons from PD patients Acta neuropathologica High 28337542
2017 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. Genetic deletion of VAPA/VAPB, structural analysis (FFAT mimic identification), mutagenesis, viral replication assays mBio High 28698274
2018 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. Proximity-based biotinylation (BioID), FRET, siRNA knockdown, colocalization assays, CD4-chimera domain mapping, KO cells Proceedings of the National Academy of Sciences High 29941597
2018 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. Affinity immunopurification + mass spectrometry from brain, Kv2.1 KO mice, VAPA KO cells, multiplex immunolabeling in brain sections The Journal of neuroscience High 30012696
2018 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. Electrophysiology (patch clamp), surface expression assays, VAPB KO zebrafish and mice, ECG recordings FASEB journal High 29879376
2019 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. Immunofluorescence, proximity ligation assay, synaptic electrophysiology, siRNA knockdown, spine morphology analysis Acta neuropathologica communications High 30841933
2019 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. Immunoelectron microscopy, rapamycin-dependent APEX2 proximity labeling, SILAC mass spectrometry The Journal of biological chemistry Medium 31519755
2019 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. siRNA knockdown, viral titer assays, immunofluorescence, immunogold electron microscopy Cells Medium 30717447
2018 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. siRNA knockdown, overexpression, Western blot for autophagy markers (LC3, p62, beclin 1), autophagic flux assays Neuroscience bulletin Medium 30143980
2022 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. Co-immunoprecipitation, phosphatase treatment, site-directed mutagenesis of phosphorylation sites, GSK3β inhibitors/activators, proximity ligation assay The Journal of cell biology High 35019937
2022 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. Co-immunoprecipitation of full-length deletion mutants, electron microscopy of ER-mitochondria contacts, Ca2+ imaging Frontiers in cell and developmental biology High 36120587
2023 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. Co-immunoprecipitation, mutagenesis of FFAT-like motif, VAPB KO mice, insulin signaling assays, glucose tolerance tests Cell discovery High 37528084
2024 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. High-speed single-molecule imaging, 3D electron microscopy, VAPB-P56S mutant analysis Nature High 38267577
2024 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. Overexpression rescue experiments, Ca2+ imaging, synaptic electrophysiology, GSK3β activity assays, pharmacological treatment with UDCA Acta neuropathologica communications High 38395965
2019 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. VAPB-depleted stable cell clones, PI4P immunofluorescence assay, neurite extension measurement, PI4K pharmacological inhibition Journal of cell science Medium 30745341
2022 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. Immunofluorescence, proximity ligation assay, co-immunoprecipitation, siRNA knockdown, live imaging Life science alliance Medium 36585258
2014 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). Drosophila reverse genetic screen (2635 genes), genetic epistasis, pharmacological rapamycin treatment Biology open Medium 25361581
2014 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. Co-immunoprecipitation, pulldown with FFAT-like motif mutants, immunofluorescence of nuclear envelope The Kobe journal of medical sciences Medium 25612670
2009 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. Co-immunoprecipitation, HCV replicon assays, siRNA knockdown, overexpression in Huh-7 cells Journal of virology Medium 19515777
2017 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. Genetic epistasis in C. elegans, RNAi suppressor screen, tissue-specific expression, co-localization imaging Development High 28634272

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. American journal of human genetics 775 15372378
2014 ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43. Nature communications 520 24893131
2011 VAPB interacts with the mitochondrial protein PTPIP51 to regulate calcium homeostasis. Human molecular genetics 475 22131369
2017 The ER-Mitochondria Tethering Complex VAPB-PTPIP51 Regulates Autophagy. Current biology : CB 343 28132811
2017 α-Synuclein binds to the ER-mitochondria tethering protein VAPB to disrupt Ca2+ homeostasis and mitochondrial ATP production. Acta neuropathologica 310 28337542
2010 SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: genotype-phenotype correlations. Journal of medical genetics 237 20577002
2016 ALS/FTD-associated FUS activates GSK-3β to disrupt the VAPB-PTPIP51 interaction and ER-mitochondria associations. EMBO reports 224 27418313
2017 ACBD5 and VAPB mediate membrane associations between peroxisomes and the ER. The Journal of cell biology 212 28108524
2007 Motor neuron disease-associated mutant vesicle-associated membrane protein-associated protein (VAP) B recruits wild-type VAPs into endoplasmic reticulum-derived tubular aggregates. The Journal of neuroscience : the official journal of the Society for Neuroscience 206 17804640
2004 ALS3 and ALS8 represent a single locus that encodes a Candida albicans adhesin; functional comparisons between Als3p and Als1p. Microbiology (Reading, England) 198 15256583
2008 The amyotrophic lateral sclerosis 8 protein VAPB is cleaved, secreted, and acts as a ligand for Eph receptors. Cell 183 18555774
2006 Characterization of amyotrophic lateral sclerosis-linked P56S mutation of vesicle-associated membrane protein-associated protein B (VAPB/ALS8). The Journal of biological chemistry 179 16891305
2011 Downregulation of VAPB expression in motor neurons derived from induced pluripotent stem cells of ALS8 patients. Human molecular genetics 176 21685205
2005 Human VAP-B is involved in hepatitis C virus replication through interaction with NS5A and NS5B. Journal of virology 173 16227268
2010 Characterization of the properties of a novel mutation in VAPB in familial amyotrophic lateral sclerosis. The Journal of biological chemistry 143 20940299
2018 Kv2 potassium channels form endoplasmic reticulum/plasma membrane junctions via interaction with VAPA and VAPB. Proceedings of the National Academy of Sciences of the United States of America 141 29941597
2008 VAPB interacts with and modulates the activity of ATF6. Human molecular genetics 138 18263603
2019 The VAPB-PTPIP51 endoplasmic reticulum-mitochondria tethering proteins are present in neuronal synapses and regulate synaptic activity. Acta neuropathologica communications 130 30841933
2009 ALS-linked P56S-VAPB, an aggregated loss-of-function mutant of VAPB, predisposes motor neurons to ER stress-related death by inducing aggregation of co-expressed wild-type VAPB. Journal of neurochemistry 120 19183264
2008 Vesicle associated membrane protein B (VAPB) is decreased in ALS spinal cord. Neurobiology of aging 115 18701194
2018 Identification of VAPA and VAPB as Kv2 Channel-Interacting Proteins Defining Endoplasmic Reticulum-Plasma Membrane Junctions in Mammalian Brain Neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 106 30012696
2024 Motion of VAPB molecules reveals ER-mitochondria contact site subdomains. Nature 94 38267577
2009 A VAPB mutant linked to amyotrophic lateral sclerosis generates a novel form of organized smooth endoplasmic reticulum. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 91 20008544
2005 A common founder for amyotrophic lateral sclerosis type 8 (ALS8) in the Brazilian population. Human genetics 88 16187141
2013 Investigating the contribution of VAPB/ALS8 loss of function in amyotrophic lateral sclerosis. Human molecular genetics 82 23446633
2008 Evolution of the Rhodococcus equi vap pathogenicity island seen through comparison of host-associated vapA and vapB virulence plasmids. Journal of bacteriology 79 18606735
2011 VapC toxins from Mycobacterium tuberculosis are ribonucleases that differentially inhibit growth and are neutralized by cognate VapB antitoxins. PloS one 78 21738782
2014 Expression of the effector protein IncD in Chlamydia trachomatis mediates recruitment of the lipid transfer protein CERT and the endoplasmic reticulum-resident protein VAPB to the inclusion membrane. Infection and immunity 75 24595143
2010 Structural requirements for VAP-B oligomerization and their implication in amyotrophic lateral sclerosis-associated VAP-B(P56S) neurotoxicity. The Journal of biological chemistry 69 20207736
2012 Secreted VAPB/ALS8 major sperm protein domains modulate mitochondrial localization and morphology via growth cone guidance receptors. Developmental cell 68 22264801
2007 Molecular epidemiology of Rhodococcus equi based on traA, vapA, and vapB virulence plasmid markers. The Journal of infectious diseases 68 17674320
2006 Expanding the phenotypes of the Pro56Ser VAPB mutation: proximal SMA with dysautonomia. Muscle & nerve 68 16967488
2017 Peroxisomal ACBD4 interacts with VAPB and promotes ER-peroxisome associations. Cell cycle (Georgetown, Tex.) 67 28463579
2008 FFAT rescues VAPA-mediated inhibition of ER-to-Golgi transport and VAPB-mediated ER aggregation. Journal of cell science 62 18713837
2012 VAPB and C9orf72 mutations in 1 familial amyotrophic lateral sclerosis patient. Neurobiology of aging 61 22878164
2014 Membrane-bound methyltransferase complex VapA-VipC-VapB guides epigenetic control of fungal development. Developmental cell 60 24871947
2013 Amyotrophic lateral sclerosis-related VAPB P56S mutation differentially affects the function and survival of corticospinal and spinal motor neurons. Human molecular genetics 60 23771029
2013 The ALS8 protein VAPB interacts with the ER-Golgi recycling protein YIF1A and regulates membrane delivery into dendrites. The EMBO journal 56 23736259
2017 Noroviruses Co-opt the Function of Host Proteins VAPA and VAPB for Replication via a Phenylalanine-Phenylalanine-Acidic-Tract-Motif Mimic in Nonstructural Viral Protein NS1/2. mBio 55 28698274
2022 Regulating peroxisome-ER contacts via the ACBD5-VAPB tether by FFAT motif phosphorylation and GSK3β. The Journal of cell biology 51 35019937
2013 Amyotrophic lateral sclerosis (ALS)-associated VAPB-P56S inclusions represent an ER quality control compartment. Acta neuropathologica communications 51 24252306
2010 AAV-mediated expression of wild-type and ALS-linked mutant VAPB selectively triggers death of motoneurons through a Ca2+-dependent ER-associated pathway. Journal of neurochemistry 51 20477942
2008 New VAPB deletion variant and exclusion of VAPB mutations in familial ALS. Neurology 48 18322265
2015 Vapb/Amyotrophic lateral sclerosis 8 knock-in mice display slowly progressive motor behavior defects accompanying ER stress and autophagic response. Human molecular genetics 46 26362257
2013 Widespread aggregation of mutant VAPB associated with ALS does not cause motor neuron degeneration or modulate mutant SOD1 aggregation and toxicity in mice. Molecular neurodegeneration 45 23281774
2013 VAPB/ALS8 MSP ligands regulate striated muscle energy metabolism critical for adult survival in caenorhabditis elegans. PLoS genetics 42 24039594
2012 A mutation in VAPB that causes amyotrophic lateral sclerosis also causes a nuclear envelope defect. Journal of cell science 40 22454507
2012 Restructured endoplasmic reticulum generated by mutant amyotrophic lateral sclerosis-linked VAPB is cleared by the proteasome. Journal of cell science 40 22611258
2021 The Link between VAPB Loss of Function and Amyotrophic Lateral Sclerosis. Cells 39 34440634
2019 Proteomic mapping by rapamycin-dependent targeting of APEX2 identifies binding partners of VAPB at the inner nuclear membrane. The Journal of biological chemistry 38 31519755
2012 Intrinsically unstructured domain 3 of hepatitis C Virus NS5A forms a "fuzzy complex" with VAPB-MSP domain which carries ALS-causing mutations. PloS one 36 22720086
2014 VAPB/ALS8 interacts with FFAT-like proteins including the p97 cofactor FAF1 and the ASNA1 ATPase. BMC biology 31 24885147
2014 Gain-of-function mutations in the ALS8 causative gene VAPB have detrimental effects on neurons and muscles. Biology open 29 24326187
2024 Modulation of ER-mitochondria tethering complex VAPB-PTPIP51: Novel therapeutic targets for aging-associated diseases. Ageing research reviews 28 38719161
2012 VAMP-associated protein B (VAPB) promotes breast tumor growth by modulation of Akt activity. PloS one 27 23049696
2015 Atypical familial amyotrophic lateral sclerosis with initial symptoms of pain or tremor in a Chinese family harboring VAPB-P56S mutation. Journal of neurology 26 26566915
2022 Disruption of the VAPB-PTPIP51 ER-mitochondria tethering proteins in post-mortem human amyotrophic lateral sclerosis. Frontiers in cell and developmental biology 25 36051435
2022 The PTPIP51 coiled-coil domain is important in VAPB binding, formation of ER-mitochondria contacts and IP3 receptor delivery of Ca2+ to mitochondria. Frontiers in cell and developmental biology 25 36120587
2014 A genetic screen identifies Tor as an interactor of VAPB in a Drosophila model of amyotrophic lateral sclerosis. Biology open 25 25361581
2020 Proteomics-Based Approach Identifies Altered ER Domain Properties by ALS-Linked VAPB Mutation. Scientific reports 24 32376919
2009 Human VAP-C negatively regulates hepatitis C virus propagation. Journal of virology 24 19515777
2000 Pathogenicity of Rhodococcus equi expressing a virulence-associated 20 kDa protein (VapB) in foals. Veterinary microbiology 24 10925043
2020 VAPB ER-Aggregates, A Possible New Biomarker in ALS Pathology. Cells 23 31936602
2007 A mutation in human VAP-B--MSP domain, present in ALS patients, affects the interaction with other cellular proteins. Protein expression and purification 23 17540579
2018 The VAMP-associated protein VAPB is required for cardiac and neuronal pacemaker channel function. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 22 29879376
2018 Loss of VAPB Regulates Autophagy in a Beclin 1-Dependent Manner. Neuroscience bulletin 22 30143980
2011 Accumulation of wildtype and ALS-linked mutated VAPB impairs activity of the proteasome. PloS one 22 21998752
2021 Pathomechanisms of ALS8: altered autophagy and defective RNA binding protein (RBP) homeostasis due to the VAPB P56S mutation. Cell death & disease 21 33972508
2006 Sporadic ALS is not associated with VAPB gene mutations in Southern Italy. Journal of negative results in biomedicine 21 16729899
2022 Lanthanum decreased VAPB-PTPP51, BAP31-FIS1, and MFN2-MFN1 expression of mitochondria-associated membranes and induced abnormal autophagy in rat hippocampus. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 20 35090998
2016 Neuronal overexpression of human VAPB slows motor impairment and neuromuscular denervation in a mouse model of ALS. Human molecular genetics 20 28173107
2024 Stimulating VAPB-PTPIP51 ER-mitochondria tethering corrects FTD/ALS mutant TDP43 linked Ca2+ and synaptic defects. Acta neuropathologica communications 19 38395965
2015 ALS-Linked P56S-VAPB Mutation Impairs the Formation of Multinuclear Myotube in C2C12 Cells. International journal of molecular sciences 18 26266407
2013 Familial adult spinal muscular atrophy associated with the VAPB gene: report of 42 cases in Brazil. Arquivos de neuro-psiquiatria 18 24212516
2024 Mitochondria-associated endoplasmic reticulum membranes tethering protein VAPB-PTPIP51 protects against ischemic stroke through inhibiting the activation of autophagy. CNS neuroscience & therapeutics 17 38584329
2014 Amyotrophic lateral sclerosis-linked mutant VAPB inclusions do not interfere with protein degradation pathways or intracellular transport in a cultured cell model. PloS one 17 25409455
2010 Novel splice variants of the amyotrophic lateral sclerosis-associated gene VAPB expressed in human tissues. Biochemical and biophysical research communications 17 20227395
2023 VAPB-mediated ER-targeting stabilizes IRS-1 signalosomes to regulate insulin/IGF signaling. Cell discovery 16 37528084
2016 Characterization of the Deep-Sea Streptomyces sp. SCSIO 02999 Derived VapC/VapB Toxin-Antitoxin System in Escherichia coli. Toxins 16 27376329
2014 Structure of Rhodococcus equi virulence-associated protein B (VapB) reveals an eight-stranded antiparallel β-barrel consisting of two Greek-key motifs. Acta crystallographica. Section F, Structural biology communications 16 25005079
2019 VAPB depletion alters neuritogenesis and phosphoinositide balance in motoneuron-like cells: relevance to VAPB-linked amyotrophic lateral sclerosis. Journal of cell science 15 30745341
2016 Oxysterol-binding protein ORP3 rescues the Amyotrophic Lateral Sclerosis-linked mutant VAPB phenotype. Experimental cell research 15 26812496
2011 The ALS8-associated mutant VAPB(P56S) is resistant to proteolysis in neurons. Journal of neurochemistry 15 21275991
2011 Amyotrophic lateral sclerosis-linked mutant VAPB enhances TDP-43-induced motor neuronal toxicity. Journal of neurochemistry 15 21933185
2022 A SNX1-SNX2-VAPB partnership regulates endosomal membrane rewiring in response to nutritional stress. Life science alliance 14 36585258
2021 Mutant VAPB: Culprit or Innocent Bystander of Amyotrophic Lateral Sclerosis? Contact (Thousand Oaks (Ventura County, Calif.)) 14 37366377
2020 lncRNA DANCR Promotes Proliferation and Metastasis of Breast Cancer Cells Through Sponging miR-4319 and Upregulating VAPB. Cancer biotherapy & radiopharmaceuticals 14 32818383
2014 VAP-B binds to Rab3GAP1 at the ER: its implication in nuclear envelope formation through the ER-Golgi intermediate compartment. The Kobe journal of medical sciences 14 25612670
2019 Host Vesicle Fusion Protein VAPB Contributes to the Nuclear Egress Stage of Herpes Simplex Virus Type-1 (HSV-1) Replication. Cells 13 30717447
2018 Nucleocytoplasmic transport defect in a North American patient with ALS8. Annals of clinical and translational neurology 13 29560381
2017 A novel mutation of VAPB in one Chinese familial amyotrophic lateral sclerosis pedigree and its clinical characteristics. Journal of neurology 13 28993872
2025 Structural and functional studies of the VAPB-PTPIP51 ER-mitochondria tethering proteins in neurodegenerative diseases. Acta neuropathologica communications 12 40045432
2023 Stay or Go: Sulfolobales Biofilm Dispersal Is Dependent on a Bifunctional VapB Antitoxin. mBio 12 37036347
2021 Role of VAPB and vesicular profiles in α-synuclein aggregates in multiple system atrophy. Brain pathology (Zurich, Switzerland) 12 34196429
2020 Characterization of the amyotrophic lateral sclerosis-linked P56S mutation of the VAPB gene in Southern Brazil. Amyotrophic lateral sclerosis & frontotemporal degeneration 12 32162544
2017 The secreted MSP domain of C. elegans VAPB homolog VPR-1 patterns the adult striated muscle mitochondrial reticulum via SMN-1. Development (Cambridge, England) 12 28634272
2015 ALS-associated P56S-VAPB mutation restrains 3T3-L1 preadipocyte differentiation. Biochemical and biophysical research communications 12 25824044
2016 C-Terminal Auto-Regulatory Motif of Hepatitis C Virus NS5B Interacts with Human VAPB-MSP to Form a Dynamic Replication Complex. PloS one 11 26784321
2022 Structural brain and spinal cord damage in symptomatic and pre-symptomatic VAPB-related ALS. Journal of the neurological sciences 10 35007920
2013 No association between VAPB mutations and familial or sporadic ALS in Sweden, Portugal and Iceland. Amyotrophic lateral sclerosis & frontotemporal degeneration 10 23971766

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