Affinage

VPS4A

Vacuolar protein sorting-associated protein 4A · UniProt Q9UN37

Length
437 aa
Mass
48.9 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: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VPS4A is the energy-providing AAA+ ATPase of the ESCRT pathway, a hexameric enzyme that disassembles ESCRT-III filaments to drive membrane constriction and fission (PMID:18687924, PMID:24161953). Its N-terminal MIT domain forms an asymmetric three-helix bundle that recognizes ESCRT-III subunits through two distinct interaction modes: it binds C-terminal MIM1 amphipathic helices of CHMP1-3-class subunits in a groove between MIT helices α2 and α3 (PMID:17928862, PMID:17928861, PMID:16174732), and binds a second MIM2 motif of subunits such as CHMP6 in an extended conformation along the groove between helices 1 and 3 (PMID:18606141). Purified VPS4A is essentially inactive and autoinhibited by its MIT domain and adjacent linker; ESCRT-III binding relieves this autoinhibition and engages substrate in the central pore to stimulate ATP hydrolysis (PMID:25833946, PMID:20805225). Active VPS4 assembles into an asymmetric spiral hexamer that processively translocates and globally unfolds ESCRT-III substrates through its central pore by a sequential, 'conveyor-belt' hydrolysis mechanism, thereby constricting and severing ESCRT-III filaments (PMID:28379137, PMID:29165244, PMID:25938660, PMID:30989108, PMID:28439563). This activity is tuned by an extensive cofactor network: LIP5/Vta1 stabilizes the active hexamer and stimulates ATPase activity via its conserved VSE/VSL elements that bridge adjacent subunits and contact VPS4 helices α7/α9 (PMID:16505166, PMID:28714467, PMID:25637630, PMID:25164817), ESCRT-III subunits Vps2 and Snf7 and the Bro1 V domain directly stimulate the enzyme (PMID:18194652, PMID:24711499, PMID:34160559), and Ist1 acts as a context-dependent inhibitor or activator depending on its partnership with Did2 (PMID:18032582, PMID:26515066). Through this machinery VPS4A executes membrane scission in MVB/intraluminal-vesicle biogenesis and cytokinetic abscission, where it concentrates at spindle poles and midbodies and is held in check by an Aurora-B/ANCHR checkpoint at the midbody ring (PMID:20616062, PMID:24814515, PMID:24711499, PMID:29019322). VPS4A additionally performs ESCRT-III-independent roles: regulation of endosomal cholesterol transport (PMID:10637304, PMID:23009658), centrosome/centriole homeostasis and ciliogenesis (PMID:29463826), and lipophagy, where phosphorylation at Ser95/97 directs it to lipid droplets and enables LC3 binding for selective autophagic degradation (PMID:39520981). De novo missense variants in the VPS4A ATPase domain cause a multisystem disorder featuring enlarged endosomal vacuoles, dyserythropoiesis with cytokinesis defects, and neurodevelopmental phenotypes (PMID:33186545, PMID:33186543).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2000 High

    Establishing that VPS4 ATPase activity gates a discrete membrane-trafficking step, the first cell-based work showed catalytically dead enzyme dominantly blocks a defined sorting process rather than acting cytosolically.

    Evidence Expression of ATPase-defective hVPS4 mutants in cultured cells with fractionation and cholesterol staining

    PMID:10637304

    Open questions at the time
    • Did not define the molecular substrate of the ATPase
    • Mechanism of membrane recruitment unknown at this stage
  2. 2001 Medium

    Resolving the gene architecture in mammals, two paralogs VPS4A and VPS4B were shown to associate with endosomes and form heteromeric complexes, framing later paralog-specific questions.

    Evidence Yeast complementation, two-hybrid, dominant-negative expression and localization

    PMID:11563910

    Open questions at the time
    • Functional division of labor between VPS4A and VPS4B not resolved
    • Oligomeric state misassigned (later corrected to hexamer)
  3. 2005 High

    To explain how VPS4 finds its targets, the MIT domain was solved and shown to recognize the C-terminal half of an ESCRT-III subunit, identifying the substrate-recruitment module.

    Evidence NMR solution structure of VPS4A MIT with CHMP1B binding and mutagenesis

    PMID:16174732

    Open questions at the time
    • Only one ESCRT-III partner tested
    • Did not address how binding couples to ATPase activation
  4. 2007 High

    Defining the MIM1 recognition code, crystal structures established the conserved amphipathic-helix motif and the reversed TPR-like binding mode, explaining ESCRT-III selectivity of the MIT domain across yeast and human.

    Evidence Crystal structures of VPS4 MIT-CHMP1A and yeast Vps4 MIT-Vps2 with mutagenesis and sorting assays

    PMID:17928861 PMID:17928862

    Open questions at the time
    • Did not explain subunits lacking MIM1
    • Did not capture the assembled hexamer-substrate complex
  5. 2008 High

    Extending the recognition repertoire, a second motif class (MIM2) bound at a distinct MIT site was identified, showing VPS4 reads multiple ESCRT-III tags relevant to HIV budding and lysosomal sorting.

    Evidence NMR structure of VPS4 MIT-CHMP6 MIM2 with HIV-1 budding and lysosomal targeting assays

    PMID:18606141

    Open questions at the time
    • Relative contributions of MIM1 vs MIM2 in vivo unresolved
    • How dual motifs coordinate on filaments not addressed
  6. 2008 High

    Demonstrating direct disassembly, reconstitution showed VPS4 binds inside ESCRT-III tubes and severs them upon ATP hydrolysis, providing the mechanistic basis for filament turnover.

    Evidence In vitro reconstitution with purified CHMP2A/CHMP3, EM, ATPase assay

    PMID:18687924

    Open questions at the time
    • Atomic mechanism of substrate engagement still unknown
    • Cofactor requirements for full activity not yet defined
  7. 2008 High

    Beginning to map cofactor control, Vta1/LIP5 was shown to stimulate ATPase activity and promote assembly, and distinct stimulation routes (Vps2 direct vs Vps60/Did2 via Vta1) were distinguished.

    Evidence In vitro ATPase assays, yeast genetics, binding studies; LIP5-CHMP co-IP/competition assays

    PMID:16505166 PMID:18194652 PMID:18385515

    Open questions at the time
    • Structural basis of Vta1 stimulation not yet known
    • Quantitative integration of multiple stimulators unresolved
  8. 2010 High

    Connecting the enzyme to cell division, depletion experiments showed VPS4 and ESCRT-III are required for cytokinetic abscission and that VPS4 localizes to spindle poles and midbodies.

    Evidence siRNA knockdown of VPS4A/B and CHMP proteins with live-cell imaging and division assays

    PMID:20616062

    Open questions at the time
    • Spatial trigger of abscission-associated VPS4 recruitment not defined
    • Centrosome phenotype mechanism unclear
  9. 2010 High

    Quantifying autoinhibition and activation, human VPS4A was shown to be intrinsically inactive and stimulated by ESCRT-III via MIM plus adjacent residues with substrate engaging the pore, and a multi-interaction assembly network was mapped.

    Evidence In vitro ATPase assays with purified human proteins and mutagenesis; systematic yeast interaction-network genetics

    PMID:20110351 PMID:20805225

    Open questions at the time
    • Structure of the active substrate-engaged hexamer not yet available
    • Order of cofactor recruitment in mammals not defined
  10. 2013 High

    Settling the oligomeric state, biophysics and crystallography established that active Vps4 is a hexamer whose assembly interface is essential for ATPase activity and function.

    Evidence Size-exclusion chromatography, analytical ultracentrifugation, crystal structures, yeast functional assays

    PMID:24161953

    Open questions at the time
    • Asymmetry and nucleotide-state coupling not yet resolved
    • Substrate path through the pore not visualized
  11. 2014 High

    Linking enzyme action to membrane geometry and division control, work showed Vps4 binding to Vps2/Snf7 drives intraluminal-vesicle scission and that an Aurora-B/ANCHR checkpoint restrains VPS4 at the midbody.

    Evidence Yeast genetics with electron tomography; co-IP, imaging, and Aurora-B inhibition in cells

    PMID:24711499 PMID:24814515

    Open questions at the time
    • How the timing signal translates to pore activity not defined
    • Molecular trigger relocating VPS4 to the abscission zone unclear
  12. 2015 High

    Defining the disassembly mechanism, biophysics demonstrated VPS4 globally unfolds ESCRT-III by threading it through the pore, and binding studies showed MIM engagement relieves MIT autoinhibition to permit central-pore substrate capture.

    Evidence HDX-MS and cysteine cross-linking; quantitative binding, cross-linking and mutagenesis; LIP5NTD crystal structure with CHMP MIMs

    PMID:25637630 PMID:25833946 PMID:25938660

    Open questions at the time
    • Step-resolved coupling of hydrolysis to translocation not yet imaged
    • CHMP5 inhibitory braking not tested in vivo
  13. 2017 High

    Achieving the mechanistic synthesis, cryo-EM of active hexamers with substrate, Vta1, and nucleotide established a sequential, processive 'conveyor-belt' translocation through an asymmetric spiral ring and the Vta1 bridging mode that promotes the active oligomer.

    Evidence Multiple cryo-EM structures (3.2-4.3 Å) of Vps4-substrate, Vps4-Vta1, and ATP-bound hexamers with biochemical/mutant-doping validation

    PMID:28379137 PMID:28439563 PMID:28714467 PMID:29165244

    Open questions at the time
    • Full-length filament constriction not captured in these structures
    • In-cell stoichiometry of functional units not established here
  14. 2017 High

    Bridging structure to cell biology, quantitative live imaging showed productive MVB budding requires multiple Vps4 hexamers with continuous ATPase-dependent component exchange, and acute disruption stalls budding.

    Evidence Lattice light-sheet microscopy and tomographic EM

    PMID:29019322

    Open questions at the time
    • Exact number and lifetime of hexamers per scission event approximate
    • Generalization to other membrane sites untested
  15. 2019 High

    Visualizing constriction directly, real-time AFM/EM showed VPS4 progressively narrows and coils CHMP2A-CHMP3 filaments into end caps before disassembly, and a cyclic-peptide structure generalized the pore translocation mechanism to hairpin and crosslinked chains.

    Evidence High-speed AFM and EM of reconstituted filaments; cryo-EM of Vps4-cyclic peptide complexes

    PMID:30989108 PMID:31184588

    Open questions at the time
    • Coupling of constriction to membrane fission not directly observed
    • Physiological substrate topology range not fully mapped
  16. 2020 Medium

    Establishing disease causation, de novo ATPase-domain variants were shown to produce enlarged endosomes with aberrant IST1 accumulation, cytokinesis/abscission failures in erythropoiesis, and defects in centrosome, cilium, nuclear membrane and chromosome segregation.

    Evidence Patient-derived fibroblasts, iPSC-derived neurons and erythroid cells, immunofluorescence, flow cytometry, dominant-negative comparison

    PMID:33186543 PMID:33186545

    Open questions at the time
    • Dominant-negative vs loss-of-function basis of variants not fully dissected
    • Tissue-specific severity determinants unknown
  17. 2022 High

    Identifying paralog-specific post-translational control, HCV-induced ROS/JNK signaling was shown to activate Itch, which polyubiquitylates VPS4A at K23/K121, enhancing CHMP1B binding and ATPase activity to promote virus release.

    Evidence siRNA, site-directed mutagenesis, co-IP, ATPase assay, JNK inhibition, HCV titer assay

    PMID:35044214

    Open questions at the time
    • Whether this ubiquitylation operates outside HCV infection unknown
    • Structural effect of K23/K121 modification on the hexamer undefined
  18. 2024 High

    Revealing a moonlighting catabolic role, VPS4A was shown to act as a selective lipophagy receptor: fasting-induced Ser95/97 phosphorylation drives lipid-droplet localization and LC3 binding for lysosomal co-degradation.

    Evidence Mouse liver phosphoproteomics, 3D imaging, co-IP, siRNA, phospho-site mutagenesis, lysosomal degradation assays; plus aloperine target-ID and CRISPR KO autophagy-flux work

    PMID:39166458 PMID:39520981

    Open questions at the time
    • Relationship between lipophagy receptor role and ESCRT ATPase activity unresolved
    • Kinase phosphorylating Ser95/97 not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the well-defined biochemical hexamer mechanism is partitioned among ESCRT-dependent scission and the ESCRT-III-independent roles (centrosome/cilium, endosomal cholesterol, lipophagy), and how VPS4A versus VPS4B specialize, remains unresolved.
  • No structural model for ESCRT-III-independent substrate engagement
  • Paralog-specific functional division not defined
  • Upstream kinases/regulators of non-ESCRT functions largely unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 4 GO:0140657 ATP-dependent activity 4 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005768 endosome 4 GO:0005764 lysosome 2 GO:0005815 microtubule organizing center 2 GO:0005811 lipid droplet 1 GO:0005829 cytosol 1
Pathway
R-HSA-1640170 Cell Cycle 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-9609507 Protein localization 3 R-HSA-9612973 Autophagy 2 R-HSA-1852241 Organelle biogenesis and maintenance 1
Partners
CHMP1BCHMP2ACHMP3CHMP4BCHMP5CHMP6IST1LIP5
Complex memberships
ESCRT-III disassembly machineryVPS4 hexamerVPS4-Vta1/LIP5 complex

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 VPS4 binds on the inside of helical tubular structures assembled in vitro by ESCRT-III proteins CHMP2A and CHMP3, and disassembles these tubes upon ATP hydrolysis, demonstrating its role in disassembling ESCRT-III helical assemblies. In vitro reconstitution with purified proteins, electron microscopy, ATPase assay Science High 18687924
2007 The MIT domain of human VPS4A binds conserved C-terminal MIM1 amphipathic helices of CHMP1-3 class ESCRT-III proteins; crystal structures of VPS4A MIT-CHMP1A complex reveal the CHMP motif binds in a groove between helices α2 and α3 of the TPR-like repeat in a reversed orientation relative to canonical TPR interactions, with three conserved leucines docking into distinct MIT pockets. Crystal structure, NMR, mutagenesis, in vitro binding assays Nature High 17928861 17928862
2007 Crystal structure of the yeast Vps4 MIT domain bound to the Vps2 C-terminus reveals that MIT helices α2 and α3 recognize a (D/E)xxLxxRLxxL(K/R) motif; only Vps2 and Did2 among six yeast ESCRT-III-related subunits bind the Vps4 MIT domain, and mutations in the motif cause sorting defects in yeast. Crystal structure, yeast two-hybrid, mutagenesis, vacuolar sorting assay Nature High 17928861
2005 The N-terminal MIT domain of VPS4A forms an asymmetric three-helix bundle resembling the first three helices of a TPR motif; it binds the C-terminal half of ESCRT-III protein CHMP1B (Kd ~20 µM); a conserved Leu-64 on helix 3 mediates CHMP1B binding by completing the TPR motif. NMR solution structure, mutagenesis, in vitro binding assay PNAS High 16174732
2008 VPS4 MIT domains bind a second MIM2 motif found in a subset of ESCRT-III subunits (e.g., CHMP6); the NMR solution structure of VPS4 MIT-CHMP6 MIM2 complex shows MIM2 elements bind in extended conformations along the groove between helices 1 and 3 of the MIT domain, distinct from the MIM1 binding site. NMR solution structure, mutagenesis, HIV-1 budding assay, lysosomal protein targeting assay Developmental Cell High 18606141
2000 ATPase-defective human VPS4 (unable to bind or hydrolyze ATP) localizes to membranes and specifically induced endocytic vacuoles, whereas wild-type hVPS4 is cytosolic; expression of mutant hVPS4 causes a kinetic block in postendosomal cholesterol sorting without affecting recycling to the TGN or recycling compartment. Transient expression of wild-type and ATPase-defective hVPS4 mutants in cultured cells, subcellular fractionation, fluorescence microscopy, cholesterol staining Molecular Biology of the Cell High 10637304
2001 Mammalian cells express two non-allelic VPS4 paralogs, VPS4-A and VPS4-B (80% identity); both associate with endosomal compartments; VPS4-A and VPS4-B form heteromeric complexes as shown by two-hybrid analysis; expression of dominant-negative VPS4-A(E228Q) or VPS4-B(E235Q) induces vacuolar protein sorting defects in yeast. Yeast complementation, two-hybrid interaction, subcellular localization (fluorescence microscopy), dominant-negative expression Journal of Molecular Biology Medium 11563910
2006 Vta1 (human SBP1/LIP5) positively regulates Vps4 by promoting proper assembly and stimulating its ATPase activity through the conserved VSL (Vta1/SBP1/LIP5) region, representing an evolutionarily conserved mechanism for regulating ESCRT disassembly. In vitro ATPase assay, yeast genetic analysis, in vivo ESCRT sorting assay Journal of Cell Biology High 16505166
2008 Two distinct mechanisms stimulate Vps4 ATPase activity: Vps2 directly stimulates Vps4 via its MIT domain, whereas Vps60 stimulates Vps4 via Vta1; Did2 can stimulate Vps4 by both mechanisms in distinct contexts. In vitro ATPase assay, protein interaction studies, yeast genetics Developmental Cell High 18194652
2007 Ist1 has a dual role in Vps4 regulation: it positively regulates Vps4 recruitment to ESCRT-III via Did2, and negatively regulates Vps4 by forming an Ist1-Vps4 heterodimer in which Vps4 cannot bind ESCRT machinery. Yeast genetic analysis, protein interaction assays, localization studies Molecular Biology of the Cell Medium 18032582
2010 Assembly of active Vps4 on ESCRT-III requires a network of at least 12 distinct interactions; the most critical interactions are with Vta1, and ESCRT-III subunits Vps2 and Snf7; a recruitment complex of Did2-Ist1-Vps4 forms in the cytoplasm and upon binding to ESCRT-III recruits Vta1, which triggers assembly of the active Vps4 oligomer. Systematic in vivo interaction network analysis, yeast genetics, localization studies Molecular Biology of the Cell Medium 20110351
2010 Depletion of VPS4A or VPS4B, or any of the 11 human ESCRT-III (CHMP) proteins, inhibits cytokinetic abscission; VPS4 proteins concentrate at spindle poles during mitosis and at midbodies during cytokinesis; depletion also alters centrosome and spindle pole numbers, producing multipolar or monopolar spindles. siRNA knockdown, live-cell fluorescence microscopy, immunofluorescence, cell division assays PNAS High 20616062
2014 ANCHR (ZFYVE19) associates with VPS4 and CHMP4C at the midbody ring in an Aurora-B-dependent manner to delay abscission; this association prevents VPS4 relocalization from the midbody ring to the abscission zone; Aurora B inactivation relieves this constraint to allow abscission. Co-immunoprecipitation, fluorescence microscopy, siRNA knockdown, Aurora-B kinase inhibition, cell division assays Nature Cell Biology High 24814515
2014 Coordinated binding of Vps4 to ESCRT-III subunits Vps2 and Snf7 is coupled to membrane neck constriction during intraluminal vesicle (ILV) formation; Vps4 alone (not ESCRT-III alone) is required to complete ILV biogenesis and membrane scission. Yeast genetics, biochemistry, electron tomography Journal of Cell Biology High 24711499
2017 Cryo-EM structure at 4.3 Å of active Vps4 hexamer with cofactor Vta1, ADP·BeFx, and ESCRT-III substrate peptide shows four Vps4 subunits forming a helix that binds substrate; Vta1 stabilizes the helix; the structure supports a 'walking' model in which ATP binding propagates helix growth at one end while hydrolysis promotes disassembly at the other, translocating ESCRT-III through the pore. Cryo-EM structure (4.3 Å resolution), biochemical assays eLife High 28379137
2017 Cryo-EM structure at 3.2 Å of Vps4 bound to ESCRT-III peptide substrate reveals the peptide adopts a β-strand conformation with helical symmetry matching the five Vps4 subunits it contacts; adjacent Vps4 subunits make equivalent interactions with successive substrate dipeptides through two classes of pore loop 1 side-chain binding pockets, supporting a 'conveyor belt' translocation model. Cryo-EM structure (3.2 Å resolution) eLife High 29165244
2015 Vps4 completely unfolds ESCRT-III substrates during disassembly (EX1 hydrogen/deuterium exchange behavior); Vps4 hexamers containing single pore-loop cysteines cross-link to cysteines in the folded core domain of ESCRT-III subunits, supporting a mechanism in which Vps4 disassembles ESCRT-III by globally unfolding substrates and threading them through the central pore. Hydrogen/deuterium exchange mass spectrometry, cysteine cross-linking, in vitro disassembly assay Nature Structural & Molecular Biology High 25938660
2017 Quantitative lattice light-sheet microscopy shows that productive MVB budding events require at least two Vps4 hexamers during ESCRT-III assembly, and that membrane budding involves continuous stochastic exchange of Vps4 and ESCRT-III components dependent on Vps4 ATPase activity; acute disruption of Vps4 recruitment by tomographic EM stalled membrane budding. Quantitative fluorescence lattice light-sheet microscopy, tomographic electron microscopy eLife High 29019322
2019 VPS4 constricts and cleaves CHMP2A-CHMP3 helical filaments in vitro as observed by high-speed atomic force microscopy and EM; constriction starts asymmetrically and progressively decreases filament diameter, coiling filaments into dome-like end caps before complete disassembly. High-speed atomic force microscopy, electron microscopy, in vitro reconstitution with purified proteins Science Advances High 30989108
2017 Cryo-EM structures of the ATP-bound Vps4E233Q hexamer (3.9 Å) and its complex with Vta1 (4.2 Å) reveal six subunits in a spiral-shaped ring; Vta1 dimer bridges two adjacent Vps4 subunits via two different interaction modes at the ring periphery to promote active Vps4 hexamer formation. Cryo-EM structure determination, single-molecule analysis, biochemical assays Nature Communications High 28714467
2013 Active wild-type yeast and archaeal Vps4 enzymes form hexamers (not dodecamers) in the presence of ATP/ADP; Vta1 binds the hexameric Vps4 without changing its oligomeric state; hexamerization interface mutations abolish ATPase activity and block Vps4p function in yeast. Size-exclusion chromatography, equilibrium analytical ultracentrifugation, crystal structures, mutagenesis, yeast functional assay Journal of Molecular Biology High 24161953
2017 Cryo-EM of hydrolysis-deficient Vps4 with ATP shows an asymmetric hexameric ring with a mobile subunit whose substrate-binding loop moves 33 Å from the top to the bottom of the central pore upon a conformational transition; mutant-doping experiments support a sequential and processive ATP hydrolysis mechanism. Cryo-EM, mutant-doping biochemical assay, ATPase activity assay Science Advances High 28439563
2015 Substrate engagement to the central pore of Vps4 is autoinhibited by the MIT domain and relieved by binding of either Type 1 (MIM1) or Type 2 (MIM2) MIT-interacting motifs; residues from helix 5 of Vps2 bind the central pore of an asymmetric Vps4 hexamer in a nucleotide-state-dependent manner. Quantitative binding assays, cross-linking, mutagenesis Journal of Biological Chemistry High 25833946
2010 Purified human VPS4A is essentially inactive but is stimulated to hydrolyze ATP by ESCRT-III proteins (CHMP2A, CHMP1B, CHMP3, CHMP4A, CHMP6, CHMP5) in a reaction requiring their MIT-interacting motifs plus ~50 adjacent residues; the MIT domain and adjacent linker autoinhibit VPS4A; pore loop mutations alter the response to ESCRT-III, consistent with substrate engagement inside the pore. In vitro ATPase assay with purified proteins, mutagenesis, liposome-based oligomerization assay Journal of Biological Chemistry High 20805225
2015 The N-terminal domain of LIP5 (LIP5NTD) stimulates VPS4 ATPase activity; CHMP5 binding to LIP5NTD strongly inhibits this stimulation via insertion of a conserved Tyr182 residue into the core of LIP5NTD; crystal structure at 1 Å of LIP5NTD bound to CHMP5 and CHMP1B MIMs reveals ESCRT-III binding-induced conformational change in LIP5NTD. Crystal structure (1 Å resolution), ATPase assay, mutagenesis Journal of Biological Chemistry High 25637630
2008 LIP5 binds to CHMP5, CHMP1B, CHMP2A, and CHMP3 but not CHMP4A or CHMP6; LIP5 binds a different region in CHMP5 than in other ESCRT-III proteins; a second VPS4 binding site exists in CHMP2A and CHMP1B allowing simultaneous binding of LIP5 and VPS4; LIP5 preferentially binds soluble CHMP5 but polymerized CHMP2A. Co-immunoprecipitation, in vitro binding assays, competition binding studies Molecular Biology of the Cell Medium 18385515
2010 VPS4/SKD1 regulates endosomal cholesterol transport independently of ESCRT-III: VPS4 knockdown in HeLa cells causes LDL-cholesterol accumulation in late endosomes/lysosomes, while depletion of any ESCRT-III component has no significant effect on endosomal cholesterol transport. siRNA knockdown, fluorescence cholesterol staining, NPC1/NPC2 localization assays Traffic Medium 23009658
2011 Dominant-negative VPS4 impairs MVB biogenesis and blocks lysosomal targeting of α-synuclein while facilitating its extracellular secretion; hypersecretion of α-synuclein in VPS4-defective cells is restored by functional disruption of recycling endosome regulator Rab11a. Dominant-negative VPS4 expression, secretion assays, Rab11a co-manipulation, immunostaining PLoS ONE Medium 22216284
2015 Vps4A facilitates the secretion of oncogenic miRNAs into exosomes and the accumulation of tumor suppressor miRNAs within HCC cells; overexpression of Vps4A inactivates the PI3K/Akt signaling pathway in hepatoma cells. Small RNA sequencing, Vps4A overexpression/knockdown, exosome isolation, PI3K/Akt pathway analysis Hepatology Medium 25503676
2019 Vps4A interacts with β-catenin and CHMP4B (identified by mass spectrometry of immunoprecipitated Vps4A complex); through this interaction, Vps4A promotes plasma membrane localization and exosome release of β-catenin; Vps4A overexpression decreases β-catenin signaling and inhibits EMT in HCC cells. Co-immunoprecipitation, mass spectrometry, siRNA knockdown, cell fractionation, EMT marker analysis Cancer Letters Medium 31059752
2002 VPS4-A directly binds the Rho family GTPase Rnd2 regardless of its nucleotide-bound state (GTP- or GDP-bound); co-expression of Rnd2 with the ATPase-defective VPS4-A(E228Q) recruits Rnd2 to VPS4-A-bound early endosomes. Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation, fluorescence microscopy Biochemical Journal Medium 11931639
2012 VPS4A and CHMP6/VPS20 interact directly with H-Ras (but not K-Ras) in endosomes in a GTP-bound and ubiquitylated state-dependent manner; repressing CHMP6 and VPS4A blocks Ras-induced transformation and impairs Ras recycling to the plasma membrane and EGFR recycling. Co-immunoprecipitation, cell fractionation, FRAP, siRNA knockdown, transformation assay Oncogene Medium 22231449
2020 De novo missense variants in the ATPase domain of VPS4A cause enlarged endosomal vacuoles; proband-derived fibroblasts show enlarged endosomal structures with abnormal accumulation of the ESCRT protein IST1 on the limiting membrane; VPS4A is also required for normal centrosome number, primary cilium morphology, nuclear membrane morphology, chromosome segregation, and mitotic spindle formation. Patient-derived fibroblasts, iPSC-derived neurons, immunofluorescence, dominant-negative VPS4A overexpression as comparison American Journal of Human Genetics Medium 33186545
2020 VPS4A mutations cause cytokinesis and abscission defects in erythropoiesis (binucleated erythroblasts, cytoplasmic bridges); VPS4A is required for reticulocyte maturation including removal of transferrin receptor (CD71) from the red blood cell membrane; iPSC-derived erythroid cells from probands recapitulate the dyserythropoietic phenotype. Bone marrow analysis, iPSC differentiation, flow cytometry (CD71), patient-derived fibroblast studies American Journal of Human Genetics Medium 33186543
2018 GFP-VPS4 is a dynamic component of both mother and daughter centrioles; ATPase-defective VPS4EQ accumulates at centrosomes and reduces γ-tubulin levels, decreases microtubule growth, eliminates centriolar satellites, and pauses ciliogenesis after ciliary vesicle formation; ESCRT-III proteins rarely localize to centrosomes and their depletion does not phenocopy VPS4EQ, indicating an ESCRT-III-independent centrosomal function. Live-cell fluorescence microscopy, FRAP, siRNA knockdown, zebrafish embryo injection, immunofluorescence Scientific Reports Medium 29463826
2022 HCV infection activates ROS/JNK signaling to phosphorylate and activate the E3 ubiquitin ligase Itch, which specifically polyubiquitylates VPS4A (at K23 and K121) but not VPS4B; this polyubiquitylation enhances the VPS4A-CHMP1B interaction, increases VPS4A ATPase activity, and promotes HCV particle release. siRNA knockdown, site-directed mutagenesis, co-immunoprecipitation, ATPase activity assay, JNK inhibition, HCV infectivity titer assay Journal of Virology High 35044214
2024 VPS4A functions as a selective receptor for lipophagy: phosphorylation of VPS4A at Ser95 and Ser97 drives its localization to lipid droplets in response to fasting; VPS4A and lipid droplets are concomitantly degraded in lysosomes in an ATG7-sensitive manner; silencing VPS4A or blocking its LC3 binding specifically inhibits lipophagy without affecting other selective autophagy pathways. Mouse liver phosphoproteomics, 3D imaging reconstruction, co-immunoprecipitation, siRNA knockdown, phosphorylation site mutagenesis, lysosomal degradation assay Molecular Cell High 39520981
2024 VPS4A is a direct target of the compound aloperine; amino acids F153 and D263 of VPS4A are confirmed as aloperine binding sites; VPS4A knockout mimics aloperine treatment, inhibiting autophagosome-lysosome fusion and blocking autophagic flux. Target identification by drug-protein interaction assays, CRISPR knockout, autophagy flux assays Advanced Science Medium 39166458
2021 The conserved V domain of Bro1 (yeast homologue of ALIX/HD-PTP) directly stimulates Vps4; this stimulatory activity is required for MVB cargo sorting; ubiquitin binding enhances V domain stimulation of Vps4 to promote intraluminal vesicle formation. In vitro ATPase assay, yeast genetics, in vivo MVB sorting assay Journal of Cell Biology Medium 34160559
2015 Ist1 can both inhibit and stimulate Vps4 ATPase activity depending on its conformation: inhibition requires both the MIM and a conserved ELYC surface; binding of the ESCRT-III partner Did2 converts Ist1 from an inhibitor to a stimulator of Vps4, coordinating Vps4 activity with the timing of ESCRT-III disassembly. In vitro ATPase assay, ESCRT-III disassembly assay, mutagenesis Journal of Biological Chemistry Medium 26515066
2014 The Vps4 stimulatory element (VSE) of Vta1 contacts Vps4 α-helices 7 and 9 of the small AAA domain to stimulate ATP hydrolysis; intergenic compensatory mutations between VSE and these Vps4 helices validate the interaction surface. Mutagenesis, ATPase assay, yeast complementation, structural modeling Journal of Biological Chemistry Medium 25164817
2014 Vfa1 binds to the MIT domain of Vps4 via its C-terminal 17 residues adopting a canonical MIM2 conformation (crystal structure determined); this interaction is high affinity and greatly stimulates Vps4 ATPase activity. Crystal structure of Vps4-MIT/Vfa1 complex, ATPase assay, SPR binding measurement Journal of Biological Chemistry High 24567329
2019 Vps4 can bind and translocate cyclic peptides in a hairpin conformation through its central pore, with one strand making primary contacts and the second returning through the pore without intimate contacts; this reveals a general mechanism for translocation of extended chains, hairpins, and crosslinked polypeptides. Cryo-EM structure of cyclic peptide complexes, binding affinity measurements eLife High 31184588

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Helical structures of ESCRT-III are disassembled by VPS4. Science (New York, N.Y.) 283 18687924
2007 ESCRT-III recognition by VPS4 ATPases. Nature 281 17928862
2007 Structural basis for selective recognition of ESCRT-III by the AAA ATPase Vps4. Nature 264 17928861
2003 Overlapping motifs (PTAP and PPEY) within the Ebola virus VP40 protein function independently as late budding domains: involvement of host proteins TSG101 and VPS-4. Journal of virology 234 12525615
2000 ATPase-defective mammalian VPS4 localizes to aberrant endosomes and impairs cholesterol trafficking. Molecular biology of the cell 228 10637304
2018 Structures, Functions, and Dynamics of ESCRT-III/Vps4 Membrane Remodeling and Fission Complexes. Annual review of cell and developmental biology 222 30095293
2014 Surveillance of nuclear pore complex assembly by ESCRT-III/Vps4. Cell 187 25303532
2010 Human ESCRT-III and VPS4 proteins are required for centrosome and spindle maintenance. Proceedings of the National Academy of Sciences of the United States of America 175 20616062
2000 TSG101/mammalian VPS23 and mammalian VPS28 interact directly and are recruited to VPS4-induced endosomes. The Journal of biological chemistry 170 11134028
2007 Hepatitis B virus maturation is sensitive to functional inhibition of ESCRT-III, Vps4, and gamma 2-adaptin. Journal of virology 156 17553870
2005 Structure and ESCRT-III protein interactions of the MIT domain of human VPS4A. Proceedings of the National Academy of Sciences of the United States of America 156 16174732
2014 Coordinated binding of Vps4 to ESCRT-III drives membrane neck constriction during MVB vesicle formation. The Journal of cell biology 147 24711499
2015 Vps4A functions as a tumor suppressor by regulating the secretion and uptake of exosomal microRNAs in human hepatoma cells. Hepatology (Baltimore, Md.) 145 25503676
2008 Two distinct modes of ESCRT-III recognition are required for VPS4 functions in lysosomal protein targeting and HIV-1 budding. Developmental cell 145 18606141
2006 Recycling of ESCRTs by the AAA-ATPase Vps4 is regulated by a conserved VSL region in Vta1. The Journal of cell biology 136 16505166
2007 Herpes simplex virus type 1 cytoplasmic envelopment requires functional Vps4. Journal of virology 135 17507493
2017 Recruitment dynamics of ESCRT-III and Vps4 to endosomes and implications for reverse membrane budding. eLife 133 29019322
2008 Respiratory syncytial virus uses a Vps4-independent budding mechanism controlled by Rab11-FIP2. Proceedings of the National Academy of Sciences of the United States of America 127 18621683
2011 The AAA-ATPase VPS4 regulates extracellular secretion and lysosomal targeting of α-synuclein. PloS one 123 22216284
2008 ESCRT-III family members stimulate Vps4 ATPase activity directly or via Vta1. Developmental cell 123 18194652
2007 Ist1 regulates Vps4 localization and assembly. Molecular biology of the cell 116 18032582
2003 A dominant negative form of the AAA ATPase SKD1/VPS4 impairs membrane trafficking out of endosomal/lysosomal compartments: class E vps phenotype in mammalian cells. Journal of cell science 115 12482925
2017 Structural basis of protein translocation by the Vps4-Vta1 AAA ATPase. eLife 111 28379137
2014 ANCHR mediates Aurora-B-dependent abscission checkpoint control through retention of VPS4. Nature cell biology 106 24814515
2014 Noncanonical role for the host Vps4 AAA+ ATPase ESCRT protein in the formation of Tomato bushy stunt virus replicase. PLoS pathogens 101 24763736
2001 Mammalian cells express two VPS4 proteins both of which are involved in intracellular protein trafficking. Journal of molecular biology 92 11563910
2010 Assembly of the AAA ATPase Vps4 on ESCRT-III. Molecular biology of the cell 90 20110351
2009 Vps4 and the ESCRT-III complex are required for the release of infectious hepatitis C virus particles. The Journal of general virology 88 19828764
2015 Vps4 disassembles an ESCRT-III filament by global unfolding and processive translocation. Nature structural & molecular biology 87 25938660
2004 Budding of PPxY-containing rhabdoviruses is not dependent on host proteins TGS101 and VPS4A. Journal of virology 85 14990685
2017 The AAA ATPase Vps4 binds ESCRT-III substrates through a repeating array of dipeptide-binding pockets. eLife 77 29165244
2010 Regulators of Vps4 ATPase activity at endosomes differentially influence the size and rate of formation of intralumenal vesicles. Molecular biology of the cell 74 20089837
2019 VPS4 triggers constriction and cleavage of ESCRT-III helical filaments. Science advances 73 30989108
2017 Aβ accumulation causes MVB enlargement and is modelled by dominant negative VPS4A. Molecular neurodegeneration 73 28835279
2007 Ubiquitin depletion and dominant-negative VPS4 inhibit rhabdovirus budding without affecting alphavirus budding. Journal of virology 71 17913808
2008 Novel interactions of ESCRT-III with LIP5 and VPS4 and their implications for ESCRT-III disassembly. Molecular biology of the cell 69 18385515
2013 The oligomeric state of the active Vps4 AAA ATPase. Journal of molecular biology 57 24161953
2010 Activation of human VPS4A by ESCRT-III proteins reveals ability of substrates to relieve enzyme autoinhibition. The Journal of biological chemistry 54 20805225
2009 Budding of filamentous and non-filamentous influenza A virus occurs via a VPS4 and VPS28-independent pathway. Virology 54 19524996
2020 De Novo VPS4A Mutations Cause Multisystem Disease with Abnormal Neurodevelopment. American journal of human genetics 53 33186545
2008 Biochemical and structural studies of yeast Vps4 oligomerization. Journal of molecular biology 52 18929572
2006 Potent inhibition of human Hepatitis B virus replication by a host factor Vps4. Virology 52 16920176
2009 Disruption of Vps4 and JNK function in Drosophila causes tumour growth. PloS one 51 19194501
2019 Vps4A mediates the localization and exosome release of β-catenin to inhibit epithelial-mesenchymal transition in hepatocellular carcinoma. Cancer letters 50 31059752
2017 Mechanism of Vps4 hexamer function revealed by cryo-EM. Science advances 49 28439563
2020 Synthetic Lethal Interaction between the ESCRT Paralog Enzymes VPS4A and VPS4B in Cancers Harboring Loss of Chromosome 18q or 16q. Cell reports 48 33326793
1997 The VPS4 gene is involved in protein transport out of a yeast pre-vacuolar endosome-like compartment. Current genetics 48 9211789
2011 Structure and function of the membrane deformation AAA ATPase Vps4. Biochimica et biophysica acta 47 21925211
2015 Asymmetric ring structure of Vps4 required for ESCRT-III disassembly. Nature communications 46 26632262
2007 Structural characterization of the ATPase reaction cycle of endosomal AAA protein Vps4. Journal of molecular biology 46 17949747
2009 Three-dimensional structure of AAA ATPase Vps4: advancing structural insights into the mechanisms of endosomal sorting and enveloped virus budding. Structure (London, England : 1993) 43 19278657
2020 Synthetic lethality between VPS4A and VPS4B triggers an inflammatory response in colorectal cancer. EMBO molecular medicine 41 31930723
2017 Cryo-EM structures of the ATP-bound Vps4E233Q hexamer and its complex with Vta1 at near-atomic resolution. Nature communications 40 28714467
2004 The Plasmodium falciparum Vps4 homolog mediates multivesicular body formation. Journal of cell science 39 15252121
2007 Sendai virus budding in the course of an infection does not require Alix and VPS4A host factors. Virology 38 17467023
2019 Structure of Vps4 with circular peptides and implications for translocation of two polypeptide chains by AAA+ ATPases. eLife 34 31184588
2015 Binding of Substrates to the Central Pore of the Vps4 ATPase Is Autoinhibited by the Microtubule Interacting and Trafficking (MIT) Domain and Activated by MIT Interacting Motifs (MIMs). The Journal of biological chemistry 33 25833946
2011 Cellular VPS4 is required for efficient entry and egress of budded virions of Autographa californica multiple nucleopolyhedrovirus. Journal of virology 33 22072775
2020 Coevolution of Eukaryote-like Vps4 and ESCRT-III Subunits in the Asgard Archaea. mBio 32 32430468
2010 A common substrate recognition mode conserved between katanin p60 and VPS4 governs microtubule severing and membrane skeleton reorganization. The Journal of biological chemistry 32 20339000
2015 A novel mechanism of regulating the ATPase VPS4 by its cofactor LIP5 and the endosomal sorting complex required for transport (ESCRT)-III protein CHMP5. The Journal of biological chemistry 30 25637630
2002 Vps4-A (vacuolar protein sorting 4-A) is a binding partner for a novel Rho family GTPase, Rnd2. The Biochemical journal 30 11931639
2024 Aloperine Suppresses Cancer Progression by Interacting with VPS4A to Inhibit Autophagosome-lysosome Fusion in NSCLC. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 29 39166458
2019 Structure and mechanism of the ESCRT pathway AAA+ ATPase Vps4. Biochemical Society transactions 29 30647138
2016 Herpes Simplex Virus Capsid Localization to ESCRT-VPS4 Complexes in the Presence and Absence of the Large Tegument Protein UL36p. Journal of virology 29 27252536
2010 Influenza virus budding does not require a functional AAA+ ATPase, VPS4. Virus research 29 20621136
2023 The patterned assembly and stepwise Vps4-mediated disassembly of composite ESCRT-III polymers drives archaeal cell division. Science advances 28 36921039
2012 CHMP6 and VPS4A mediate the recycling of Ras to the plasma membrane to promote growth factor signaling. Oncogene 28 22231449
2012 The AAA ATPase VPS4/SKD1 regulates endosomal cholesterol trafficking independently of ESCRT-III. Traffic (Copenhagen, Denmark) 28 23009658
2006 Cholesterol depletion facilitates ubiquitylation of NPC1 and its association with SKD1/Vps4. Journal of cell science 27 16757520
2003 Comparative sequence and expression analyses of four mammalian VPS4 genes. Gene 27 12594041
2017 The VPS4 component of the ESCRT machinery plays an essential role in HPV infectious entry and capsid disassembly. Scientific reports 26 28349933
2008 The Sulfolobus solfataricus AAA protein Sso0909, a homologue of the eukaryotic ESCRT Vps4 ATPase. Biochemical Society transactions 26 18208393
2006 The role of the VPS4A-exosome pathway in the intrinsic egress route of a DNA-binding anticancer drug. Pharmaceutical research 26 16841193
2013 Relief of autoinhibition enhances Vta1 activation of Vps4 via the Vps4 stimulatory element. The Journal of biological chemistry 25 23880759
2008 Candida albicans VPS4 is required for secretion of aspartyl proteases and in vivo virulence. Mycopathologia 25 18814053
2022 Hepatitis C Virus-Induced ROS/JNK Signaling Pathway Activates the E3 Ubiquitin Ligase Itch to Promote the Release of HCV Particles via Polyubiquitylation of VPS4A. Journal of virology 24 35044214
2020 VPS4A Mutations in Humans Cause Syndromic Congenital Dyserythropoietic Anemia due to Cytokinesis and Trafficking Defects. American journal of human genetics 24 33186543
2018 VPS4 is a dynamic component of the centrosome that regulates centrosome localization of γ-tubulin, centriolar satellite stability and ciliogenesis. Scientific reports 24 29463826
2021 miR-4454 Promotes Hepatic Carcinoma Progression by Targeting Vps4A and Rab27A. Oxidative medicine and cellular longevity 23 34777698
2007 Vps4 regulates a subset of protein interactions at the multivesicular endosome. The FEBS journal 23 17408385
2007 Regulation of HTLV-1 Gag budding by Vps4A, Vps4B, and AIP1/Alix. Virology journal 23 17601348
1999 Cloning, characterisation, and functional expression of the Mus musculus SKD1 gene in yeast demonstrates that the mouse SKD1 and the yeast VPS4 genes are orthologues and involved in intracellular protein trafficking. Gene 23 10393249
2021 Bro1 stimulates Vps4 to promote intralumenal vesicle formation during multivesicular body biogenesis. The Journal of cell biology 21 34160559
2019 Rapid depletion of ESCRT protein Vps4 underlies injury-induced autophagic impediment and Wallerian degeneration. Science advances 21 30788439
2024 VPS4A is the selective receptor for lipophagy in mice and humans. Molecular cell 20 39520981
2021 The ESCRT-III protein VPS4, but not CHMP4B or CHMP2B, is pathologically increased in familial and sporadic ALS neuronal nuclei. Acta neuropathologica communications 18 34281622
2022 Nucleoporins are degraded via upregulation of ESCRT-III/Vps4 complex in Drosophila models of C9-ALS/FTD. Cell reports 17 36130523
2015 Conformational Changes in the Endosomal Sorting Complex Required for the Transport III Subunit Ist1 Lead to Distinct Modes of ATPase Vps4 Regulation. The Journal of biological chemistry 17 26515066
2007 A functional analysis of the Candida albicans homolog of Saccharomyces cerevisiae VPS4. FEMS yeast research 17 17506830
2014 Vps4 stimulatory element of the cofactor Vta1 contacts the ATPase Vps4 α7 and α9 to stimulate ATP hydrolysis. The Journal of biological chemistry 16 25164817
2015 Drosophila Vps4 promotes Epidermal growth factor receptor signaling independently of its role in receptor degradation. Development (Cambridge, England) 15 25790850
2015 The AAA ATPase Vps4 Plays Important Roles in Candida albicans Hyphal Formation and is Inhibited by DBeQ. Mycopathologia 15 26700222
2016 Structural Fine-Tuning of MIT-Interacting Motif 2 (MIM2) and Allosteric Regulation of ESCRT-III by Vps4 in Yeast. Journal of molecular biology 14 27075672
2014 Vfa1 binds to the N-terminal microtubule-interacting and trafficking (MIT) domain of Vps4 and stimulates its ATPase activity. The Journal of biological chemistry 14 24567329
2009 Regulation of Vps4 ATPase activity by ESCRT-III. Biochemical Society transactions 14 19143619
2023 Toxoplasma gondii scavenges mammalian host organelles through the usurpation of host ESCRT-III and Vps4A. Journal of cell science 11 36718630
2019 Disrupting the association of Autographa californica multiple nucleopolyhedrovirus Ac93 with cellular ESCRT-III/Vps4 hinders nuclear egress of nucleocapsids and intranuclear microvesicles formation. Virology 11 32056718
2014 Candida albicans VPS4 contributes differentially to epithelial and mucosal pathogenesis. Virulence 11 25483774
2008 The Vps4 C-terminal helix is a critical determinant for assembly and ATPase activity and has elements conserved in other members of the meiotic clade of AAA ATPases. The FEBS journal 11 18266866

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