Affinage

VAPB

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

Length
243 aa
Mass
27.2 kDa
Annotated
2026-04-28
100 papers in source corpus 38 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VAPB is a tail-anchored ER-resident adaptor protein that organizes membrane contact sites between the ER and multiple organelles — mitochondria, peroxisomes, the plasma membrane, endosomes, and the nuclear envelope — by recruiting FFAT-motif-containing and FFAT-like-motif-containing partner proteins (including PTPIP51, ACBD5, ACBD4, CERT, IRS-1, Kv2 channels, Rab3GAP1, and SNX2) through its cytosolic MSP domain (PMID:17804640, PMID:22131369, PMID:28108524, PMID:29941597, PMID:37528084). The VAPB–PTPIP51 tether at ER–mitochondria contact sites mediates IP3 receptor-dependent Ca²⁺ transfer from ER to mitochondria, thereby regulating mitochondrial ATP production, autophagosome formation, and synaptic activity; this tether is dynamically regulated by GSK-3β-dependent phosphorylation and is disrupted by ALS/FTD-associated proteins TDP-43, FUS, and α-synuclein (PMID:22131369, PMID:28132811, PMID:24893131, PMID:28337542, PMID:30841933). The MSP domain is also proteolytically cleaved and secreted as a ligand for Eph and Lar-like receptors, promoting Arp2/3-dependent actin remodeling and mitochondrial positioning in striated muscle (PMID:18555774, PMID:22264801). The P56S missense mutation in the MSP domain causes ALS type 8 by inducing MSP misfolding, aggregation into organized smooth ER inclusions, dominant-negative sequestration of wild-type VAPB, loss of FFAT-motif binding, and impaired ER–mitochondria contact site dynamics (PMID:15372378, PMID:17804640, PMID:20008544, PMID:38267577).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2004 Medium

    Identifying the P56S mutation in VAPB's MSP domain as causative for familial ALS8 established VAPB as a disease gene and implicated it in intracellular membrane trafficking, but its precise molecular function was unknown.

    Evidence Genetic mapping and mutation identification in ALS8 families

    PMID:15372378

    Open questions at the time
    • No biochemical function defined
    • No interacting partners identified
    • Mechanism linking VAPB to motor neuron degeneration unknown
  2. 2006 High

    Demonstrating that VAPB promotes the IRE1-XBP1 UPR pathway and that P56S abolishes this activity while sequestering wild-type VAPB established both a loss-of-function and dominant-negative mechanism for the ALS mutation.

    Evidence siRNA knockdown, overexpression, UPR reporter assays, subcellular fractionation in cell lines

    PMID:16891305

    Open questions at the time
    • Whether UPR modulation is direct or indirect was unclear
    • No structural basis for P56S aggregation
  3. 2007 High

    Showing that VAPB recruits FFAT-motif-containing lipid-binding proteins to the ER surface via its MSP domain defined the core molecular function, while demonstrating P56S aggregation into immobile ER clusters that trap wild-type VAPA/VAPB explained the dominant-negative disease mechanism.

    Evidence Co-immunoprecipitation, shRNA knockdown, live-cell imaging in primary neurons

    PMID:17804640

    Open questions at the time
    • Identity of physiologically relevant FFAT partners beyond lipid-binding proteins unknown
    • Structural basis of FFAT recognition not resolved
  4. 2008 High

    The discovery that the MSP domain is cleaved and secreted as a ligand for Eph receptors — and that the ALS-linked mutation abolishes secretion — revealed a non-cell-autonomous signaling function for VAPB, extending its biology beyond ER-resident adaptor roles.

    Evidence Multi-organism studies (Drosophila, C. elegans, human), secretion assays, Eph receptor binding

    PMID:18555774

    Open questions at the time
    • Protease responsible for MSP cleavage unidentified
    • Physiological relevance of Eph signaling by MSP in mammalian neurons unclear
  5. 2008 High

    Parallel work showed VAPB modulates ER-to-Golgi transport via microtubule association and interacts with the UPR sensor ATF6, broadening its role in ER organization and stress signaling.

    Evidence Live-cell imaging, in vitro ER budding assay, Co-IP with ATF6, transport reporter assays

    PMID:18263603 PMID:18713837

    Open questions at the time
    • Whether ATF6 interaction is FFAT-mediated was not determined
    • Relationship between microtubule binding and FFAT-dependent functions unclear
  6. 2009 High

    Structural studies established that P56S-VAPB inserts normally into ER membranes but rapidly forms organized smooth ER (OSER) inclusions, and that it acts as a functional null that sequesters wild-type VAPB through high-affinity MSP-domain interactions, providing the biophysical basis for dominant-negative toxicity.

    Evidence Cell-free translocation, electron microscopy of OSER, yeast inositol-auxotrophy functional assay, Co-IP

    PMID:19183264 PMID:20008544

    Open questions at the time
    • Atomic-resolution structure of P56S MSP domain not available
    • Whether OSER formation occurs in vivo in ALS patients was unknown
  7. 2010 High

    Dissecting VAPB oligomerization revealed that the coiled-coil domain mediates higher-order assembly while P56S exposes hydrophobic patches in the MSP domain that enhance aggregation, separating the oligomerization and FFAT-binding interfaces.

    Evidence Systematic domain deletion/mutation, aggregation assays, FFAT binding assays

    PMID:20207736

    Open questions at the time
    • Whether coiled-coil-mediated oligomerization is regulated in vivo unknown
    • Stoichiometry of VAP complexes at contact sites not defined
  8. 2011 High

    Identification of PTPIP51 as the outer mitochondrial membrane partner of VAPB established the first molecularly defined ER-mitochondria tethering complex, with functional Ca²⁺ transfer readouts demonstrating that this tether mediates ER-to-mitochondria calcium signaling.

    Evidence Co-immunoprecipitation, siRNA knockdown, Ca²⁺ imaging, subcellular fractionation, electron microscopy

    PMID:22131369

    Open questions at the time
    • How IP3 receptors coordinate with the VAPB-PTPIP51 tether was not resolved
    • Whether additional bridging factors exist at these contacts
  9. 2012 High

    Two discoveries expanded VAPB's contact-site biology: secreted MSP signals through Lar-like receptors and Arp2/3 to control mitochondrial positioning in muscle, while at the ER, VAPB facilitates retrograde transport to the nuclear envelope — both disrupted by disease mutations.

    Evidence C. elegans/Drosophila genetics with epistasis, receptor binding; siRNA knockdown with nuclear envelope marker colocalization and FFAT rescue

    PMID:22264801 PMID:22454507

    Open questions at the time
    • Whether MSP-Lar signaling operates in mammalian muscle unknown
    • Mechanism of VAPB's role in nuclear envelope protein transport not fully resolved
  10. 2012 High

    Demonstrating that P56S-VAPB aggregates are cleared by p97/VCP-mediated proteasomal degradation (not autophagy) connected two ALS-linked proteins mechanistically and defined the quality control pathway for misfolded VAPB.

    Evidence Inducible expression system, proteasome inhibitors, dominant-negative p97/VCP, pulse-chase

    PMID:22611258

    Open questions at the time
    • E3 ubiquitin ligase targeting P56S-VAPB not identified
    • Whether proteasomal clearance is sufficient in neurons in vivo unclear
  11. 2014 High

    Discovery that TDP-43 disrupts the VAPB-PTPIP51 tether via GSK-3β activation provided a convergent mechanism linking multiple ALS/FTD-associated genes through ER-mitochondria contact site disruption and Ca²⁺ dyshomeostasis.

    Evidence Co-immunoprecipitation, Ca²⁺ imaging, electron microscopy, GSK-3β inhibition

    PMID:24893131

    Open questions at the time
    • Direct phosphorylation target of GSK-3β in the VAPB-PTPIP51 complex not identified at this point
    • Whether this mechanism operates in patient motor neurons was not shown
  12. 2017 High

    Multiple studies converged to show that the VAPB-PTPIP51 tether is a central node: it regulates autophagy via Ca²⁺ delivery to mitochondria, is disrupted by FUS and α-synuclein (expanding the pathway to Parkinson's disease), and VAPB tethers peroxisomes to the ER via ACBD5/ACBD4 — establishing VAPB as a general organelle contact site organizer.

    Evidence siRNA, overexpression, artificial tethers, autophagy flux, Ca²⁺/ATP measurement, iPSC-derived neurons, peroxisome EM and motility assays

    PMID:27418313 PMID:28108524 PMID:28132811 PMID:28337542 PMID:28463579

    Open questions at the time
    • Whether autophagy regulation by VAPB-PTPIP51 operates in neurons in vivo
    • Relative contribution of ACBD5 vs ACBD4 to peroxisome-ER contacts not determined
  13. 2018 High

    VAPB was shown to be recruited to ER-plasma membrane junctions by Kv2.1/Kv2.2 potassium channels through phosphorylation-dependent non-canonical FFAT motifs, and to modulate HCN pacemaker channel surface expression — revealing VAPB as a regulator of neuronal and cardiac excitability.

    Evidence BioID, FRET, siRNA, affinity purification/MS from brain, VAPB KO mice and zebrafish electrophysiology

    PMID:29879376 PMID:29941597 PMID:30012696

    Open questions at the time
    • Whether VAPB affects Kv2 channel gating or solely clustering unknown
    • Mechanism by which VAPB promotes HCN surface expression not resolved
  14. 2019 High

    Proximity proteomics at the inner nuclear membrane identified VAPB as a resident of the INM interacting with emerin, TMEM43, and ELYS, while functional studies showed VAPB-PTPIP51 contacts at synapses are activity-regulated and required for dendritic spine morphology.

    Evidence Immuno-EM, APEX2 proximity labeling/SILAC, PLA at synapses, electrophysiology, siRNA

    PMID:30841933 PMID:31519755

    Open questions at the time
    • Function of VAPB at the INM beyond nuclear envelope formation unknown
    • How neuronal activity signals to increase VAPB-PTPIP51 contacts not defined
  15. 2022 High

    Phosphorylation-dependent regulation of VAPB binding was defined at two contact sites: GSK-3β phosphorylates ACBD5's FFAT-like motif to regulate peroxisome-ER contacts, while the PTPIP51 coiled-coil domain (not its FFAT motif) was shown to be essential for VAPB binding in full-length protein context.

    Evidence Systematic mutagenesis, GSK-3β inhibition, Co-IP with deletion mutants, EM, Ca²⁺ imaging

    PMID:35019937 PMID:36120587

    Open questions at the time
    • Whether other kinases regulate VAPB-partner interactions at ER-mitochondria contacts
    • Structural basis of PTPIP51 coiled-coil recognition by VAPB unknown
  16. 2023 High

    VAPB was shown to directly anchor IRS-1 to the ER via an FFAT-like motif, stabilizing insulin/IGF-1 signalosomes; VAPB knockout mice displayed glucose intolerance, establishing a metabolic role for VAPB beyond neurodegeneration.

    Evidence Co-IP with FFAT mutagenesis, VAPB KO mice, glucose tolerance testing, IGF-1 stimulation

    PMID:37528084

    Open questions at the time
    • Whether metabolic dysfunction contributes to ALS8 pathology unknown
    • Other metabolic signaling pathways affected by VAPB loss not explored
  17. 2024 High

    Single-molecule tracking revealed that individual VAPB molecules transit through ER-mitochondria contact sites on a seconds timescale while the contact itself persists, and that ALS-mutant VAPB impairs this dynamic remodeling — providing the first nanoscale view of contact site architecture and its disruption in disease.

    Evidence High-speed single-molecule imaging, 3D electron microscopy, diffusion landscape mapping

    PMID:38267577

    Open questions at the time
    • Whether dynamic subdomains exist at other VAPB-mediated contact sites (peroxisome, PM)
    • Molecular determinants of VAPB dwell time at contacts not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the identity of the protease that cleaves the MSP domain for secretion, the structural basis of VAPB's selective recognition of canonical vs. non-canonical FFAT motifs, how VAPB's multiple contact site functions are coordinated in neurons, and whether pharmacological stabilization of the VAPB-PTPIP51 tether can rescue motor neuron degeneration in vivo.
  • Protease for MSP cleavage unknown
  • No high-resolution structure of full-length VAPB or VAPB-FFAT complex in a membrane context
  • In vivo therapeutic rescue of VAPB-PTPIP51 pathway in ALS models not demonstrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0048018 receptor ligand activity 3 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005783 endoplasmic reticulum 5 GO:0005635 nuclear envelope 3 GO:0005576 extracellular region 2 GO:0005739 mitochondrion 2 GO:0005886 plasma membrane 2 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-382551 Transport of small molecules 4 R-HSA-1643685 Disease 3 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-112316 Neuronal System 2 R-HSA-9612973 Autophagy 2
Partners
ACBD4ACBD5CERTFAF1IRS1KV2.1PTPIP51YIF1A
Complex memberships
VAP-A/VAP-B heterodimerVAPB-ACBD5 ER-peroxisome tetherVAPB-PTPIP51 ER-mitochondria tether

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 VAPB is identified as a vesicle-trafficking/intracellular membrane protein; a P56S missense mutation in the MSP domain causes familial motor neuron disease (ALS8), implying VAPB has a role in intracellular membrane trafficking. Genetic mapping, mutation identification, clinical/haplotype analysis American journal of human genetics Medium 15372378
2007 VAPB (and VAPA) interact with lipid-binding proteins carrying the FFAT motif via its N-terminal MSP domain, anchoring them to the cytosolic surface of the ER. The ALS-linked P56S mutation causes aggregation of mutant VAPB into immobile tubular ER clusters, perturbs FFAT-motif binding, and traps endogenous VAPA and VAPB in mutant aggregates. Knockdown or expression of mutant VAPB in primary neurons causes Golgi dispersion and cell death. Immunoprecipitation, shRNA knockdown, live-cell imaging, primary neuron culture The Journal of neuroscience High 17804640
2008 The MSP domain of VAPB interacts with the ER-localized transcription factor ATF6; overexpression of VAPB or VAPB(P56S) attenuates ATF6-regulated transcription, indicating VAP proteins modulate ER stress signalling through direct ATF6 interaction. Co-immunoprecipitation, transcription reporter assays, overexpression and mutant analysis Human molecular genetics Medium 18263603
2008 The MSP domains of VAP proteins (human VAPB/ALS8, Drosophila VAP33, C. elegans VPR-1) are cleaved and secreted as ligands for Eph receptors. The ALS-linked P58S mutation in Drosophila VAP33 abolishes MSP domain secretion, causes ubiquitination, ER inclusion accumulation, and triggers the unfolded protein response. Genetic studies in Drosophila and C. elegans, cell biology, secretion assays, Eph receptor binding assays Cell High 18555774
2006 VAPB promotes the unfolded protein response (UPR/IRE1-XBP1 pathway); siRNA knockdown of VAPB attenuates UPR to ER stress, while overexpression promotes UPR. The P56S mutation causes VAPB misfolding, aggregate formation in non-ER fractions, and nullifies VAPB's ability to mediate UPR, also causing sequestration of wild-type VAPB into aggregates. siRNA knockdown, overexpression, subcellular fractionation, UPR reporter assays The Journal of biological chemistry High 16891305
2005 VAPB (VAP-B) interacts with hepatitis C virus NS5A and NS5B via its MSP and coiled-coil domains, forms homo- and heterodimers with VAP-A through the transmembrane domain, and colocalizes with NS5A at the ER and Golgi. VAP-B enhances HCV RNA replication; knockdown reduces NS5B expression and HCV replication. Yeast two-hybrid, immunoprecipitation, mutation analysis, siRNA knockdown, HCV replicon assay Journal of virology High 16227268
2009 P56S-VAPB is functionally a null mutant in vivo (confirmed by yeast inositol-auxotrophy assay). The MSP domain of P56S-VAPB interacts with wild-type VAPB with high affinity, causing preferential recruitment of wild-type VAPB into cytosolic aggregates and attenuating normal VAPB function in UPR. P56S-VAPB expression increases vulnerability of NSC34 motoneuronal cells to ER stress-induced death. Yeast functional assay, co-immunoprecipitation, cell death assays Journal of neurochemistry High 19183264
2009 P56S-VAPB inserts post-translationally into ER membranes (like wild-type) but rapidly clusters to form inclusions that remain continuous with the ER. Ultrastructural analysis reveals inclusions represent a novel form of organized smooth ER (OSER) consisting of parallel cisternae interleaved by an electron-dense cytosolic layer. Cell-free translocation assay, confocal imaging, electron microscopy FASEB journal High 20008544
2010 VAP-B oligomerization is mainly mediated by its coiled-coil domain; the GXXXG motif in the transmembrane domain mediates TM self-association but is insufficient for full oligomerization. The P56S mutation induces conformational changes in the MSP domain exposing hydrophobic patches, enhancing oligomerization-driven aggregation without directly affecting FFAT binding. Domain deletion/mutation analysis, biochemical aggregation assays, FFAT binding assays The Journal of biological chemistry High 20207736
2011 VAPB interacts with the outer mitochondrial membrane protein PTPIP51 and is a mitochondria-associated membrane (MAM) protein. Loss of either VAPB or PTPIP51 perturbs mitochondrial Ca2+ uptake following ER store release. ALS-linked VAPB(P56S) has altered binding to PTPIP51 and increases mitochondrial Ca2+ uptake after ER release. Co-immunoprecipitation, siRNA knockdown, Ca2+ imaging, subcellular fractionation, electron microscopy Human molecular genetics High 22131369
2008 VAPB overexpression (but not the VAPA isoform) causes formation of large ER aggregates. Overexpression of VAPA inhibits ER-to-Golgi transport of membrane proteins and lateral diffusion of membrane proteins via stable microtubule association. FFAT motif expression rescues ER-to-Golgi transport and resolves VAPB-P56S aggregates by competing with VAP-microtubule association. Live-cell imaging, membrane transport assays, in vitro ER vesicle budding, microtubule co-sedimentation Journal of cell science High 18713837
2012 VAPB is required for retrograde transport to the nuclear envelope: VAPB-P56S mutation blocks transport of nucleoporins and emerin to the nuclear envelope by sequestering them in ER-Golgi intermediate compartments (ERGIC). FFAT motif overexpression restores nuclear envelope transport. VAPB knockdown alone recapitulates this phenotype. Immunofluorescence, siRNA knockdown, FFAT overexpression rescue, compartment marker co-localization Journal of cell science High 22454507
2012 P56S-VAPB inclusions are cleared by the proteasome (not macroautophagy), involving the AAA ATPase p97/VCP for extraction from aggregates. Shortly after synthesis, mutant VAPB forms small polyubiquitinated clusters that congregate independently of microtubule integrity. Inducible stable cell lines, proteasome inhibitors, dominant-negative p97/VCP, pulse-chase, immunofluorescence Journal of cell science High 22611258
2013 VAPB interacts with YIF1A (an ER-Golgi recycling protein) via transmembrane regions; YIF1A localizes to ER-Golgi intermediate compartments (ERGICs) in hippocampal neurons. VAPB is required for intracellular membrane trafficking into dendrites and normal dendritic morphology. VAPB-P56S recruits YIF1A into clusters, disrupting its ERGIC localization. Co-immunoprecipitation, live neuron imaging, siRNA knockdown, confocal microscopy The EMBO journal High 23736259
2014 VAPB interacts with the ER-resident protein CERT via its FFAT domain, and the C. trachomatis effector protein IncD expressed in the inclusion membrane recruits CERT and subsequently VAPB to the inclusion, establishing an ER contact site. Conditional FLAG-tagged IncD expression in C. trachomatis, immunofluorescence, domain mutation analysis Infection and immunity Medium 24595143
2014 VAPB interacts with p97 cofactor FAF1 and the ASNA1 ATPase subunit of the TRC complex via non-canonical FFAT-like motifs. FAF1-VAPB interaction mediates VAPB association with p97 and with ubiquitinated proteins; FAF1 siRNA reduces VAPB interaction with ubiquitinated species. This links two ALS-associated proteins (VAPB and p97). Co-immunoprecipitation, siRNA knockdown, mass spectrometry, domain mutation analysis BMC biology Medium 24885147
2014 TDP-43 (ALS/FTD-associated) disrupts the VAPB-PTPIP51 interaction and loosens ER-mitochondria associations. This is linked to disruption of cellular Ca2+ homeostasis. TDP-43 overexpression activates GSK-3β, and GSK-3β regulates the VAPB-PTPIP51 interaction. Co-immunoprecipitation, siRNA knockdown, Ca2+ imaging, electron microscopy, GSK-3β inhibition Nature communications High 24893131
2017 VAPB-PTPIP51 ER-mitochondria tethers regulate autophagy: tightening contacts (VAPB/PTPIP51 overexpression or artificial tether) impairs autophagosome formation, while loosening contacts (siRNA loss) stimulates it. The mechanism involves VAPB-PTPIP51-mediated delivery of Ca2+ from ER to mitochondria. siRNA knockdown, overexpression, artificial ER-mitochondria tether, autophagy flux assays, Ca2+ imaging Current biology High 28132811
2017 α-Synuclein binds directly to VAPB and overexpression of wild-type or PD-mutant α-synuclein disrupts VAPB-PTPIP51 tethers, loosening ER-mitochondria associations and impairing Ca2+ exchange and mitochondrial ATP production. Co-immunoprecipitation, proximity ligation assay, Ca2+ imaging, mitochondrial ATP measurement, iPSC-derived neurons Acta neuropathologica High 28337542
2017 FUS (ALS/FTD-linked) disrupts the VAPB-PTPIP51 interaction and ER-mitochondria associations via activation of GSK-3β; FUS expression impairs mitochondrial Ca2+ uptake and ATP production. Co-immunoprecipitation, Ca2+ imaging, ATP measurement, GSK-3β inhibition assays, electron microscopy EMBO reports High 27418313
2017 VAPB interacts with the peroxisomal membrane protein ACBD5 via ACBD5's FFAT motif; this ACBD5-VAPB interaction regulates ER-peroxisome membrane contact sites. Loss of this association perturbs peroxisome membrane expansion and increases peroxisome movement. Co-immunoprecipitation, siRNA knockdown, electron microscopy, live-cell imaging, peroxisome motility assays The Journal of cell biology High 28108524
2017 ACBD4 (peroxisomal membrane protein) interacts with VAPB at the ER to promote ER-peroxisome associations. Co-immunoprecipitation, fluorescence colocalization, peroxisome-ER contact quantification Cell cycle Medium 28463579
2018 VAPB interacts with Kv2.1 and Kv2.2 voltage-gated potassium channels via a non-canonical VAP-binding motif in the Kv2 C-terminus (PRC motif, phosphorylation-dependent), and this interaction recruits VAPB to ER-plasma membrane junctions. The association of VAPA/VAPB with Kv2 channels underlies the formation and organization of neuronal ER-PM contact sites. Proximity biotinylation (BioID), FRET, siRNA knockdown, colocalization/redistribution assays, CD4 chimera domain mapping Proceedings of the National Academy of Sciences High 29941597
2018 VAPB is identified as a prominent Kv2.1-associated protein in brain. VAPB and VAPA co-localize with Kv2.1 and Kv2.2 at ER-PM junctions in brain neurons in situ and in cultured neurons. VAPA KO reduces Kv2.1 clustering. The association requires an FFAT-binding domain on VAPA/VAPB and a non-canonical phosphorylation-dependent FFAT motif (PRC motif) on Kv2.1. Affinity immunopurification, mass spectrometry proteomics, KO mice, multiplex immunolabeling, colocalization The Journal of neuroscience High 30012696
2019 VAPB and PTPIP51 localize to neuronal synapses and form contacts there. Stimulating neuronal activity increases ER-mitochondria contacts and the VAPB-PTPIP51 interaction. siRNA loss of VAPB or PTPIP51 perturbs synaptic function and dendritic spine morphology. Immunofluorescence, proximity ligation assay, siRNA knockdown, electrophysiology/synaptic assays, confocal imaging Acta neuropathologica communications High 30841933
2018 VAPB is an essential modulator of HCN1 and HCN2 pacemaker channels: VAPB significantly increases HCN2 currents and surface expression, and influences dendritic neuronal distribution of HCN2. VAPB-deficient zebrafish and VAPB-/- mice exhibit severe cardiac bradycardia and altered ECG T-wave morphology. Electrophysiology, VAPB KO mice, VAPB-deficient zebrafish, surface expression assays FASEB journal High 29879376
2019 VAPB localizes to the inner nuclear membrane (INM) in addition to the ER. Proximity proteomics (rapamycin-dependent APEX2 targeting + SILAC) identifies emerin, TMEM43, and ELYS as proximity partners of VAPB at the INM/nuclear pore complex. Immunoelectron microscopy, modified APEX2 proximity labeling, SILAC mass spectrometry The Journal of biological chemistry High 31519755
2022 ACBD5-VAPB peroxisome-ER tethering is regulated by phosphorylation of ACBD5's FFAT-like motif. Phosphorylation sites in the flanking regions and core of the FFAT-like motif differentially alter VAPB binding. GSK-3β regulates ACBD5-VAPB interaction and thus peroxisome-ER contact site formation. Co-immunoprecipitation, phosphorylation site mutation, GSK-3β inhibition, peroxisome-ER contact quantification, mass spectrometry The Journal of cell biology High 35019937
2022 The PTPIP51 coiled-coil domain (not the FFAT motif) is essential for VAPB binding in the context of full-length proteins in cells, for forming ER-mitochondria contacts, and for IP3 receptor-mediated Ca2+ delivery to mitochondria. Co-immunoprecipitation with deletion mutants, electron microscopy, Ca2+ imaging Frontiers in cell and developmental biology High 36120587
2023 VAPB directly interacts with IRS-1 via a FFAT-like motif (Y745/Y746) on IRS-1 and targets IRS-1 to the ER, stabilizing IRS-1 signalosomes. IGF-1 enhances VAPB-IRS-1 association. VAPB ablation in mice leads to IRS-1 downregulation, suppressed insulin signaling, and glucose intolerance. Co-immunoprecipitation, VAPB knockout mice, mutagenesis, IGF-1 stimulation, glucose tolerance testing, live-cell imaging Cell discovery High 37528084
2024 High-speed single-molecule tracking combined with 3D EM reveals that VAPB molecules enter and leave ER-mitochondria contact sites (ERMCSs) within seconds, while the contact site itself remains stable over longer timescales. Dynamic VAPB subdomains correlate with ER membrane curvature and undergo rapid remodeling. The ALS-linked VAPB mutation perturbs these subdomains, impairing ERMCS remodeling capacity. High-speed single-molecule imaging, 3D electron microscopy, diffusion landscape mapping, ALS mutant comparison Nature High 38267577
2014 VAP-B binds Rab3GAP1 (catalytic subunit of Rab3GAP) at the ER via an FFAT-like motif of Rab3GAP1. This interaction is implicated in nuclear envelope formation through the ERGIC; a single amino acid substitution in the FFAT-like motif reduces VAPB binding and increases Rab3GAP1 binding to ERGIC-53. Co-immunoprecipitation, mutagenesis, nuclear envelope formation assay, ERGIC marker colocalization The Kobe journal of medical sciences Medium 25612670
2012 VAPB MSP domains secreted by neurons signal through Lar-like protein-tyrosine phosphatase and Roundabout receptors on striated muscle, promoting Arp2/3-dependent actin remodeling and mitochondrial localization to actin-rich I-bands. VAPB mutant C. elegans exhibit mitochondrial localization, morphology, motility, and fission/fusion defects suppressible by Lar-like receptor or Arp2/3 inactivation. C. elegans and Drosophila genetics, epistasis analysis, receptor binding assays, live mitochondria imaging Developmental cell High 22264801
2017 In C. elegans, neuronal secretion of VAPB MSP domain (vMSP) signals through CLR-1 (Lar-like receptor) on muscle, and SMN-1 acts downstream as an effector to promote Arp2/3-mediated actin nucleation and mitochondrial localization to I-bands in striated muscle. C. elegans genetics, RNAi suppressor screen, tissue-specific rescue, colocalization Development High 28634272
2019 VAPB is present at the nuclear membrane co-localizing with HSV-1 pUL34; VAPB knockdown significantly reduces cell-associated and supernatant virus titers and reduces cytoplasmic accumulation of virus particles while increasing nuclear encapsidated viral DNA, indicating VAPB facilitates HSV-1 nuclear egress. Immunogold-EM confirmed VAPB association with primary enveloped HSV-1 particles. siRNA knockdown, virus titer assays, immunogold electron microscopy, confocal colocalization Cells Medium 30717447
2024 Overexpression of VAPB or PTPIP51 to enhance ER-mitochondria contacts corrects mutant TDP43-induced damage to IP3 receptor-mediated Ca2+ delivery to mitochondria and synaptic dysfunction. Ursodeoxycholic acid (UDCA) corrects TDP43-induced damage to the VAPB-PTPIP51 interaction via inhibition of GSK-3β. Overexpression rescue, Ca2+ imaging, synaptic function assays, GSK-3β activity measurement, pharmacological treatment Acta neuropathologica communications High 38395965
2022 SNX2 (endosomal partner of SNX1) interacts with VAPB at ER subdomains during starvation, facilitating endosomal tubule tethering to VAPB-positive ER subregions important for autophagosome biogenesis. Immunofluorescence colocalization, knockdown, starvation assay, autophagy flux measurement Life science alliance Medium 36585258
2019 VAPB depletion in NSC34 motoneuron-like cells increases Golgi- and acidic vesicle-localized PI4P and reduces neurite extension upon differentiation. PI4 kinase inhibitors rescue neurite elongation, revealing VAPB regulates phosphoinositide homeostasis and neuritogenesis. Stable VAPB-depleted clones, PI4P immunostaining, PI4 kinase inhibitors, neurite length measurement Journal of cell science Medium 30745341

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 773 15372378
2014 ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43. Nature communications 513 24893131
2011 VAPB interacts with the mitochondrial protein PTPIP51 to regulate calcium homeostasis. Human molecular genetics 472 22131369
2017 The ER-Mitochondria Tethering Complex VAPB-PTPIP51 Regulates Autophagy. Current biology : CB 340 28132811
2017 α-Synuclein binds to the ER-mitochondria tethering protein VAPB to disrupt Ca2+ homeostasis and mitochondrial ATP production. Acta neuropathologica 307 28337542
2010 SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: genotype-phenotype correlations. Journal of medical genetics 235 20577002
2016 ALS/FTD-associated FUS activates GSK-3β to disrupt the VAPB-PTPIP51 interaction and ER-mitochondria associations. EMBO reports 222 27418313
2017 ACBD5 and VAPB mediate membrane associations between peroxisomes and the ER. The Journal of cell biology 207 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 178 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 171 16227268
2010 Characterization of the properties of a novel mutation in VAPB in familial amyotrophic lateral sclerosis. The Journal of biological chemistry 142 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 137 18263603
2019 The VAPB-PTPIP51 endoplasmic reticulum-mitochondria tethering proteins are present in neuronal synapses and regulate synaptic activity. Acta neuropathologica communications 128 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 114 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 105 30012696
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
2024 Motion of VAPB molecules reveals ER-mitochondria contact site subdomains. Nature 88 38267577
2005 A common founder for amyotrophic lateral sclerosis type 8 (ALS8) in the Brazilian population. Human genetics 87 16187141
2013 Investigating the contribution of VAPB/ALS8 loss of function in amyotrophic lateral sclerosis. Human molecular genetics 82 23446633
2011 VapC toxins from Mycobacterium tuberculosis are ribonucleases that differentially inhibit growth and are neutralized by cognate VapB antitoxins. PloS one 77 21738782
2008 Evolution of the Rhodococcus equi vap pathogenicity island seen through comparison of host-associated vapA and vapB virulence plasmids. Journal of bacteriology 76 18606735
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 73 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
2017 Peroxisomal ACBD4 interacts with VAPB and promotes ER-peroxisome associations. Cell cycle (Georgetown, Tex.) 67 28463579
2007 Molecular epidemiology of Rhodococcus equi based on traA, vapA, and vapB virulence plasmid markers. The Journal of infectious diseases 67 17674320
2006 Expanding the phenotypes of the Pro56Ser VAPB mutation: proximal SMA with dysautonomia. Muscle & nerve 67 16967488
2012 VAPB and C9orf72 mutations in 1 familial amyotrophic lateral sclerosis patient. Neurobiology of aging 61 22878164
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
2008 FFAT rescues VAPA-mediated inhibition of ER-to-Golgi transport and VAPB-mediated ER aggregation. Journal of cell science 60 18713837
2014 Membrane-bound methyltransferase complex VapA-VipC-VapB guides epigenetic control of fungal development. Developmental cell 58 24871947
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 54 28698274
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
2022 Regulating peroxisome-ER contacts via the ACBD5-VAPB tether by FFAT motif phosphorylation and GSK3β. The Journal of cell biology 49 35019937
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 35 22720086
2014 VAPB/ALS8 interacts with FFAT-like proteins including the p97 cofactor FAF1 and the ASNA1 ATPase. BMC biology 30 24885147
2014 Gain-of-function mutations in the ALS8 causative gene VAPB have detrimental effects on neurons and muscles. Biology open 29 24326187
2012 VAMP-associated protein B (VAPB) promotes breast tumor growth by modulation of Akt activity. PloS one 27 23049696
2024 Modulation of ER-mitochondria tethering complex VAPB-PTPIP51: Novel therapeutic targets for aging-associated diseases. Ageing research reviews 26 38719161
2015 Atypical familial amyotrophic lateral sclerosis with initial symptoms of pain or tremor in a Chinese family harboring VAPB-P56S mutation. Journal of neurology 25 26566915
2014 A genetic screen identifies Tor as an interactor of VAPB in a Drosophila model of amyotrophic lateral sclerosis. Biology open 25 25361581
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 24 36120587
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
2022 Disruption of the VAPB-PTPIP51 ER-mitochondria tethering proteins in post-mortem human amyotrophic lateral sclerosis. Frontiers in cell and developmental biology 23 36051435
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
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 18 38395965
2015 ALS-Linked P56S-VAPB Mutation Impairs the Formation of Multinuclear Myotube in C2C12 Cells. International journal of molecular sciences 18 26266407
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
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 17 35090998
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
2013 Familial adult spinal muscular atrophy associated with the VAPB gene: report of 42 cases in Brazil. Arquivos de neuro-psiquiatria 17 24212516
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
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
2016 Characterization of the Deep-Sea Streptomyces sp. SCSIO 02999 Derived VapC/VapB Toxin-Antitoxin System in Escherichia coli. Toxins 15 27376329
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
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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
2022 A SNX1-SNX2-VAPB partnership regulates endosomal membrane rewiring in response to nutritional stress. Life science alliance 13 36585258
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
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
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
2020 Characterization of the amyotrophic lateral sclerosis-linked P56S mutation of the VAPB gene in Southern Brazil. Amyotrophic lateral sclerosis & frontotemporal degeneration 11 32162544
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
2025 Structural and functional studies of the VAPB-PTPIP51 ER-mitochondria tethering proteins in neurodegenerative diseases. Acta neuropathologica communications 10 40045432
2022 Structural brain and spinal cord damage in symptomatic and pre-symptomatic VAPB-related ALS. Journal of the neurological sciences 10 35007920
2010 Human VAPA and the yeast VAP Scs2p with an altered proline distribution can phenocopy amyotrophic lateral sclerosis-associated VAPB(P56S). Biochemical and biophysical research communications 10 21144830