Affinage

VPS45

Vacuolar protein sorting-associated protein 45 · UniProt Q9NRW7

Round 2 corrected
Length
570 aa
Mass
65.1 kDa
Annotated
2026-04-28
130 papers in source corpus 10 papers cited in narrative 10 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VPS45 is a Sec1/Munc18 (SM)-family protein that promotes SNARE-mediated membrane fusion in endosomal and TGN-to-prevacuolar trafficking pathways. Crystallographic and NMR studies show that VPS45 binds the Qa-SNARE Tlg2/syntaxin-16 via its short N-terminal peptide, holding the SNARE in an open conformation with its domain 3a hairpin unfurled to expose the R-SNARE binding site and facilitate template complex assembly (PMID:12110575, PMID:32804076). VPS45 is constitutively complexed with Rabenosyn-5, a divalent Rab4/Rab5 effector that recruits VPS45 to early endosomes in a PI3-kinase-dependent manner and is required for β1 integrin recycling and fibroblast migration (PMID:11062261, PMID:19931244). Biallelic loss-of-function mutations in human VPS45 cause a congenital immunodeficiency syndrome with severe neutropenia, bone marrow fibrosis, and nephromegaly, establishing VPS45-dependent endosomal trafficking as essential for neutrophil survival and function (PMID:23738510).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1998 High

    The initial question of where VPS45 acts in the secretory pathway was resolved by showing that yeast Vps45p is required specifically for fusion of Golgi-derived vesicles with the prevacuolar compartment, upstream of Vps27p, and dispensable for endocytic delivery to the same compartment.

    Evidence Genetic epistasis using vps45/vps27 mutants with vacuolar morphology and vesicle accumulation readouts in S. cerevisiae

    PMID:9650782

    Open questions at the time
    • Mammalian pathway placement not yet established
    • Cognate SNARE partner for Vps45p not identified
  2. 2000 High

    The mechanism by which VPS45 is recruited to endosomal membranes was established through the discovery of its constitutive complex with Rabenosyn-5, a FYVE-domain-containing Rab5 effector that bridges VPS45 to Rab5 and PI3K-dependent lipid signals.

    Evidence Co-immunoprecipitation, mass spectrometry identification, FYVE-dependent recruitment assay, and cathepsin D processing in mammalian cells

    PMID:11062261

    Open questions at the time
    • Direct binding interface between VPS45 and Rabenosyn-5 undefined
    • Whether Rabenosyn-5 interacts with additional Rab GTPases unknown
  3. 2002 High

    The SNARE-binding mode of VPS45 was elucidated: Tlg2/syntaxin-16 binds VPS45 via a short N-terminal peptide rather than a closed-conformation mechanism, establishing a widespread SM–syntaxin coupling mechanism distinct from the Munc18-1/syntaxin-1 paradigm. Concurrently, Rabenosyn-5 was shown to be a divalent Rab4/Rab5 effector, connecting the VPS45 complex to both early-endosomal and recycling-endosomal Rab domains.

    Evidence NMR spectroscopy and biochemical pulldowns for the Tlg2–Vps45 interaction; yeast two-hybrid, co-IP, and transferrin recycling assays for Rab4/Rab5 divalency

    PMID:11788822 PMID:12110575

    Open questions at the time
    • No crystal structure of the Vps45–Tlg2 complex yet
    • Whether the open conformation of Tlg2 directly templates SNARE complex assembly not demonstrated
  4. 2008 High

    In vivo validation that VPS45, Rabenosyn, the syntaxin Avalanche, and Rab5 form a functionally obligate module for early endosome fusion was provided by Drosophila genetics, where loss of any component produced identical ultrastructural defects, epithelial polarity loss, and neoplastic transformation.

    Evidence Drosophila null mutant analysis with electron microscopy, immunofluorescence, and genetic epistasis

    PMID:18685079

    Open questions at the time
    • Whether tumor-suppressive role extends to mammals unknown
    • Molecular ordering of Rab5→Rabenosyn→VPS45→Avalanche not formally tested in this system
  5. 2009 High

    The functional requirement for the VPS45–Rabenosyn-5 interaction was demonstrated: VPS45 depletion destabilizes Rabenosyn-5 and syntaxin-16, impairs β1 integrin recycling and fibroblast migration, and causes Golgi condensation, effects rescued only by wild-type Rabenosyn-5 and not a VPS45-binding-deficient mutant.

    Evidence siRNA knockdown with domain-specific rescue constructs, β1 integrin recycling and migration assays in mammalian fibroblasts

    PMID:19931244

    Open questions at the time
    • Whether VPS45 has Rabenosyn-5-independent functions at the Golgi unclear
    • Retromer accumulation phenotype not mechanistically resolved
  6. 2013 High

    Human disease relevance was established when biallelic VPS45 mutations (T224N, E238K) were shown to cause congenital neutropenia with bone marrow fibrosis and nephromegaly; patient cells phenocopied siRNA knockdown findings (reduced Rabenosyn-5 and syntaxin-16, impaired β1 integrin surface expression, increased apoptosis), and zebrafish vps45 deficiency reproduced myeloid cell loss.

    Evidence Whole-exome sequencing of patient families, immunoblotting, flow cytometry, zebrafish morpholino model, wild-type VPS45 gene correction rescue

    PMID:23738510

    Open questions at the time
    • How VPS45 loss specifically triggers apoptosis versus trafficking dysfunction not resolved
    • Genotype–phenotype correlation across different VPS45 mutations incomplete
  7. 2018 High

    The scope of VPS45 function was extended to ciliary membrane homeostasis: in C. elegans, VPS-45 and RABS-5 regulate cilium length, periciliary membrane composition, and polycystin-2 ciliary levels through control of periciliary endocytic vesicle dynamics.

    Evidence C. elegans loss-of-function genetics with quantitative fluorescence imaging of ciliary and periciliary markers

    PMID:29572244

    Open questions at the time
    • Whether this ciliary role is conserved in mammalian primary cilia untested
    • Mechanism linking early endosome fusion to periciliary membrane remodeling not defined
  8. 2020 High

    The structural basis for the VPS45–Tlg2 interaction was resolved at atomic resolution: the crystal structure showed VPS45 holds Tlg2 in an open conformation with domain 3a unfurled to expose the R-SNARE binding site, establishing that SM proteins use mechanistically distinct modes to engage Qa-SNAREs.

    Evidence X-ray crystallography of the yeast Vps45–Tlg2 complex with in vitro reconstitution showing rescue of Tlg2 from homo-tetramers

    PMID:32804076

    Open questions at the time
    • Structure of VPS45 bound to a fully assembled four-helix SNARE bundle not available
    • Whether the unfurled domain 3a hairpin is required for template complex formation not tested by mutagenesis

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how VPS45 transitions from holding the open Qa-SNARE to chaperoning full SNARE complex assembly, whether VPS45's apparent Golgi-related and retromer-accumulation phenotypes reflect a Rabenosyn-5-independent function, and the precise mechanism by which VPS45 loss triggers neutrophil apoptosis in human disease.
  • No reconstituted assay for VPS45-catalyzed SNARE complex assembly
  • Retromer phenotype mechanism unresolved
  • Apoptotic pathway downstream of VPS45 loss not identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005768 endosome 4 GO:0031410 cytoplasmic vesicle 3 GO:0005794 Golgi apparatus 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 5 R-HSA-1643685 Disease 1 R-HSA-9612973 Autophagy 1
Partners
RAB4ARAB5ASTX16STX6ZFYVE20
Complex memberships
VPS45–Rabenosyn-5 complexVPS45–syntaxin-16 (Tlg2) complex

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 hVPS45 (the human Sec1-like SM protein) is constitutively complexed with Rabenosyn-5, a novel Rab5 effector containing a FYVE finger domain. Rabenosyn-5 serves as a molecular bridge between Rab5 and hVPS45 (since hVPS45 does not interact directly with Rab5), and both proteins are recruited to early endosomes in a phosphatidylinositol-3-kinase-dependent fashion. Overexpression of Rabenosyn-5 inhibits cathepsin D processing, indicating a specific role distinct from EEA1 in endosomal trafficking. Co-immunoprecipitation, mass spectrometry identification, FYVE-domain-dependent membrane recruitment assay, dominant-negative overexpression with functional readout (cathepsin D processing) The Journal of cell biology High 11062261
2002 Tlg2p (yeast TGN/endosomal syntaxin) and its mammalian homolog syntaxin-16 bind tightly to the SM protein Vps45p via a short N-terminal peptide motif; NMR and biochemical experiments showed that Tlg2p does not adopt a closed autoinhibited conformation (unlike syntaxin-1), and the Tlg2p/Vps45p interaction mode resembles that of Sly1p with Ufe1p/Sed5p, representing a widespread syntaxin–SM protein coupling mechanism. NMR spectroscopy, in vitro binding assays, biochemical pulldown The EMBO journal High 12110575
1998 In Saccharomyces cerevisiae, Vps45p (a Sec1p-like SM protein) is required for fusion of Golgi-derived vesicles with the prevacuolar compartment (acting upstream of Vps27p), but is not required for delivery of endocytosed proteins to the prevacuolar compartment from the plasma membrane, demonstrating that Vps45p function is restricted to a single biosynthetic vesicular pathway (Golgi-to-prevacuolar compartment). Genetic epistasis analysis using vps45 and vps27 mutants, vacuolar morphology assays, vesicle accumulation analysis European journal of cell biology High 9650782
2008 In Drosophila, Rabenosyn (Rbsn) is a Rab5 effector that bridges an interaction between Rab5 and the SM protein Vps45, and Vps45 activity targets the syntaxin Avalanche (Avl). Rbsn, Vps45, Avl, and Rab5 all localize specifically to early endosomes and are each required for vesicle fusion to form early endosomes; loss of any of these four proteins produces identical ultrastructural defects, loss of epithelial polarity, and neoplastic tumor formation, identifying Vps45 as a tumor suppressor in this context. Drosophila null mutant analysis, ultrastructural electron microscopy, immunofluorescence localization, genetic epistasis Molecular biology of the cell High 18685079
2009 In mammalian cells, a novel sequence within Rabenosyn-5 mediates its direct interaction with hVps45. hVps45 depletion causes proteasomal degradation of Rabenosyn-5, reduces Syntaxin16 expression and alters Syntaxin6 localization, and impairs β1 integrin recycling and fibroblast cell migration. Re-introduction of wild-type Rabenosyn-5 but not a Vps45-binding-deficient mutant rescues β1 integrin recycling, demonstrating that the Vps45–Rabenosyn-5 interaction is functionally required. Unlike Rabenosyn-5 depletion, hVps45 depletion causes Golgi condensation and retromer subunit accumulation near the Golgi. siRNA knockdown, rescue with siRNA-resistant wild-type vs. mutant constructs, β1 integrin recycling assay, fibroblast migration assay, immunofluorescence Experimental cell research High 19931244
2013 Biallelic mutations in VPS45 (Thr224Asn or Glu238Lys) cause a congenital neutrophil defect syndrome characterized by neutropenia, bone marrow fibrosis, and nephromegaly. Mutant cells show reduced VPS45 protein levels, reduced levels of binding partners Rabenosyn-5 and Syntaxin-16, reduced surface β1 integrin on neutrophils and fibroblasts, impaired fibroblast motility, and increased apoptosis. A zebrafish vps45-deficiency model shows marked paucity of myeloperoxidase-positive cells. Transfection with wild-type VPS45 corrects the migration defect and reduces apoptosis, establishing VPS45-dependent endosomal trafficking as essential for neutrophil function. Whole-exome sequencing, immunoblotting, immunofluorescence, electron microscopy, flow cytometry, fibroblast motility assay, apoptosis measurement, zebrafish model, gene correction experiment The New England journal of medicine High 23738510
2018 In Caenorhabditis elegans, the early endosome maturation factors RABS-5 (Rabenosyn-5) and VPS-45 (VPS45) regulate cilium length and morphology, periciliary membrane volume, and ciliary polycystin-2 (PKD-2) levels and associated sensory behaviour. VPS-45 and RABS-5 control periciliary vesicle number and levels of endocytic markers WDFY-2 and CAV-1 (caveolin-1), and CAV-1 itself also controls PKD-2 ciliary levels, linking VPS45 function to periciliary endocytic processing and ciliary membrane homeostasis. C. elegans genetics, confocal imaging, quantitative fluorescence microscopy of ciliary markers, behavioural assays The EMBO journal High 29572244
2018 In the pathogenic fungus Cryptococcus neoformans, Vps45 regulates endocytic trafficking and SNARE interactions, and is additionally required for iron uptake via high-affinity transport: a vps45 deletion mutant fails to transport the Cfo1 ferroxidase from plasma membrane to vacuole. Unexpectedly, a Vps45-GFP fusion protein co-localizes with MitoTracker and the vps45 mutant shows altered mitochondrial membrane potential and enhanced sensitivity to electron transport inhibitors, indicating a novel role for Vps45 in mitochondrial function and calcium homeostasis. The mutant also shows altered capsule polysaccharide attachment and attenuated virulence in a mouse model. Deletion mutant analysis, GFP fusion co-localization with MitoTracker, mitochondrial membrane potential assay, iron-limited growth assay, mouse virulence model PLoS pathogens Medium 30071112
2020 Crystal structure of the yeast SM protein Vps45 in complex with the Qa-SNARE Tlg2 reveals that Vps45 holds Tlg2 in an open conformation with its SNARE motif disengaged from its Habc domain and its linker region unfolded—opposite to the closed conformation induced by Munc18-1 on syntaxin-1. The domain 3a helical hairpin of Vps45 is unfurled, exposing the presumptive R-SNARE binding site to allow template complex formation. Vps45 can rescue Tlg2 from homo-tetramers into stoichiometric Vps45-Tlg2 complexes, demonstrating that SM proteins engage Qa-SNAREs via at least two mechanistically distinct modes. X-ray crystallography (structure determination), in vitro biochemical reconstitution, stoichiometry analysis of Vps45-Tlg2 complexes eLife High 32804076
2002 Rabenosyn-5 functions as a divalent Rab effector, binding both Rab5 and Rab4, thereby connecting distinct endosomal domains. This interaction is relevant to the VPS45 complex since Rabenosyn-5 is the molecular linker between Rab GTPases and hVPS45. Rabenosyn-5 overexpression accelerates transferrin recycling to the cell surface and reduces transport to Rab11-containing perinuclear recycling endosomes in a Rab4-binding-dependent manner. Yeast two-hybrid, Co-immunoprecipitation, transferrin recycling assay, dominant-negative overexpression Nature cell biology Medium 11788822

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
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2020 A reference map of the human binary protein interactome. Nature 849 32296183
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2000 Rabenosyn-5, a novel Rab5 effector, is complexed with hVPS45 and recruited to endosomes through a FYVE finger domain. The Journal of cell biology 292 11062261
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2002 Divalent Rab effectors regulate the sub-compartmental organization and sorting of early endosomes. Nature cell biology 268 11788822
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2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
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2020 H1 histones control the epigenetic landscape by local chromatin compaction. Nature 142 33299182
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2019 Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms. Nature cell biology 137 31871319
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2013 A congenital neutrophil defect syndrome associated with mutations in VPS45. The New England journal of medicine 102 23738510
2006 The H1 histamine receptor regulates allergic lung responses. The Journal of clinical investigation 100 16680192
2017 Histone HIST1H1C/H1.2 regulates autophagy in the development of diabetic retinopathy. Autophagy 89 28409999
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2018 The Sec1/Munc18 (SM) protein Vps45 is involved in iron uptake, mitochondrial function and virulence in the pathogenic fungus Cryptococcus neoformans. PLoS pathogens 26 30071112
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2020 The Sec1/Munc18 protein Vps45 holds the Qa-SNARE Tlg2 in an open conformation. eLife 23 32804076
2005 Gene regulation by histone H1: new links to DNA methylation. Cell 23 16377556
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2019 ITCH nuclear translocation and H1.2 polyubiquitination negatively regulate the DNA damage response. Nucleic acids research 20 30517763
2016 Histone H1 Limits DNA Methylation in Neurospora crassa. G3 (Bethesda, Md.) 20 27172195
2016 Extracellular vesicles shed by melanoma cells contain a modified form of H1.0 linker histone and H1.0 mRNA-binding proteins. International journal of oncology 20 27633859
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2009 Regulators affecting the metastasis suppressor activity of Nm23-H1. Molecular and cellular biochemistry 19 19377884