Affinage

VPS53

Vacuolar protein sorting-associated protein 53 homolog · UniProt Q5VIR6

Length
832 aa
Mass
94.4 kDa
Annotated
2026-04-28
17 papers in source corpus 5 papers cited in narrative 5 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VPS53 is a subunit of the GARP (Golgi-associated retrograde protein) tethering complex that mediates retrograde vesicle trafficking from endosomes to the trans-Golgi network. Its C-terminal domain adopts a tandem alpha-helical bundle fold with a conserved surface patch that directly contacts endosome-derived vesicles; mutations in this patch impair membrane trafficking (PMID:20660722). Loss-of-function mutations in VPS53 cause accumulation of swollen CD63-positive late endosomal/lysosomal compartments in human fibroblasts and are linked to progressive cerebello-cerebral atrophy, a neurodegenerative disorder (PMID:24577744, PMID:31418091).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2010 High

    Determining how the GARP complex physically engages vesicles, the crystal structure of the Vps53 C-terminal domain revealed a tandem alpha-helical bundle fold with a conserved surface patch essential for binding endosome-derived vesicles, establishing VPS53 as a direct vesicle-contact subunit within multi-subunit tethering complexes.

    Evidence X-ray crystallography at 2.9 Å resolution combined with site-directed mutagenesis and functional membrane traffic assays in yeast

    PMID:20660722

    Open questions at the time
    • Identity of the vesicle-side receptor(s) recognized by the conserved surface patch is unknown
    • Full-length VPS53 structure within the assembled GARP complex has not been determined
    • Relative contributions of VPS53 versus other GARP subunits to vesicle capture remain unresolved
  2. 2014 Medium

    Establishing VPS53's physiological relevance in human cells, loss-of-function VPS53 mutations were shown to cause abnormal accumulation of swollen CD63-positive late endosomal compartments in patient fibroblasts, linking VPS53 to a Mendelian neurodegenerative disorder (progressive cerebello-cerebral atrophy).

    Evidence Genome-wide linkage analysis, whole-exome sequencing, and immunofluorescence microscopy of fibroblasts from affected individuals

    PMID:24577744

    Open questions at the time
    • Rescue experiment (re-expression of wild-type VPS53 in patient cells) was not performed
    • The specific cargo molecules mis-sorted due to VPS53 deficiency in human cells were not identified
    • How endosomal accumulation leads to neurodegeneration is not mechanistically defined
  3. 2019 Low

    Extending the phenotypic spectrum, a homozygous VPS53 missense variant was linked to lysosomal dysfunction with impaired cholesterol and sphingolipid homeostasis, suggesting that GARP-mediated retrograde trafficking is required for lipid metabolite recycling.

    Evidence Whole-exome sequencing with clinical phenotyping of affected siblings

    PMID:31418091

    Open questions at the time
    • No direct biochemical assay of cholesterol or sphingolipid trafficking was performed
    • Whether the missense variant destabilizes the GARP complex or specifically disrupts lipid cargo sorting is unknown
    • Independent replication in additional families or model organisms is lacking
  4. 2020 Low

    VPS53 overexpression in colorectal cancer cells suppressed proliferation and invasion while promoting autophagy via Beclin 1 and LC3BII upregulation, placing VPS53 upstream of autophagy induction, though the link to GARP-mediated trafficking was not established.

    Evidence CCK-8, transwell, electron microscopy, and Western blotting in CRC cell lines with autophagy inhibitor rescue

    PMID:33116643

    Open questions at the time
    • No connection to GARP complex function or retrograde trafficking was demonstrated
    • Overexpression artifacts cannot be excluded; endogenous loss-of-function was not tested
    • Single-lab study without independent confirmation

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the identity of the vesicle-side binding partner(s) for the VPS53 conserved surface patch, the structural basis for full GARP complex assembly around VPS53, and the mechanistic pathway by which VPS53 deficiency leads to neurodegeneration.
  • No reconstituted system has defined the minimal requirements for VPS53-dependent vesicle tethering
  • Cell-type-specific roles of VPS53 in neurons versus other tissues remain unexplored
  • Whether VPS53 functions outside the GARP complex is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 1
Localization
GO:0005768 endosome 2 GO:0005794 Golgi apparatus 2 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-9609507 Protein localization 2
Complex memberships
GARP complex

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 The C-terminal fragment of Vps53 (part of the GARP complex) adopts a structure consisting of two alpha-helical bundles arranged in tandem, with a highly conserved surface patch required for binding endosome-derived vesicles and membrane traffic; mutations of this surface result in defects in membrane trafficking. The fold is structurally similar to subunits of Dsl1, conserved oligomeric Golgi, and exocyst tethering complexes, suggesting shared evolutionary origin. X-ray crystallography (2.9 Å resolution) combined with site-directed mutagenesis and functional membrane traffic assays Proceedings of the National Academy of Sciences of the United States of America High 20660722
2014 Loss-of-function mutations in VPS53 (c.2084A>G and c.1556+5G>A), predicted to disrupt the C-terminal domain critical for GARP complex function, cause abnormal accumulation of swollen, numerous CD63-positive vesicular bodies (likely intermediate recycling/late endosomes) in patient fibroblasts, demonstrating VPS53's role in retrograde endosome-to-TGN vesicle trafficking in human cells. Genome-wide linkage analysis, whole exome sequencing, and immunofluorescent microscopy of patient fibroblasts Journal of medical genetics Medium 24577744
2019 VPS53, as a component of the GARP complex, is involved in intracellular cholesterol transport and sphingolipid homeostasis in lysosomes; homozygous VPS53 p.Gln695Arg mutation causes lysosomal dysfunction consistent with impaired cholesterol trafficking, implicated in neurodegenerative processes. Whole exome sequencing of affected siblings with clinical phenotyping; mechanistic inference from GARP complex biology Neurogenetics Low 31418091
2020 VPS53 overexpression in colorectal cancer cells suppresses proliferation, migration, and invasion while promoting autophagy, associated with upregulation of Beclin 1 and LC3BII; an autophagy inhibitor attenuates these effects, placing VPS53 upstream of autophagy induction. CCK-8 assay, flow cytometry, transwell assay, electron microscopy, and Western blotting in CRC cell lines with VPS53 overexpression and autophagy inhibitor treatment OncoTargets and therapy Low 33116643
2018 The herbal medicine GZFLW increases VPS53 protein levels in endometrial stromal cells by promoting VPS53 protein stability (post-translational stabilization), and elevated VPS53 is associated with increased apoptosis in these cells. iTRAQ proteomics (LC-MS/MS) and Western blot in human endometrial stromal cells treated with GZFLW Evidence-based complementary and alternative medicine : eCAM Low 30643524

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 VPS53 mutations cause progressive cerebello-cerebral atrophy type 2 (PCCA2). Journal of medical genetics 70 24577744
2010 Structure of a C-terminal fragment of its Vps53 subunit suggests similarity of Golgi-associated retrograde protein (GARP) complex to a family of tethering complexes. Proceedings of the National Academy of Sciences of the United States of America 32 20660722
2007 The tail-anchoring domain of Bfl1 and HCCS1 targets mitochondrial membrane permeability to induce apoptosis. Journal of cell science 25 17666431
2011 HCCS1-armed, quadruple-regulated oncolytic adenovirus specific for liver cancer as a cancer targeting gene-viro-therapy strategy. Molecular cancer 23 22040050
2008 HCCS1 overexpression induces apoptosis via cathepsin D and intracellular calcium, and HCCS1 disruption in mice causes placental abnormality. Cell death and differentiation 17 18511934
2002 Candidate tumor suppressor, HCCS-1, is downregulated in human cancers and induces apoptosis in cervical cancer. International journal of cancer 16 11857354
2019 VPS53 gene is associated with a new phenotype of complicated hereditary spastic paraparesis. Neurogenetics 13 31418091
2008 Adenovirus-mediated HCCS1 overexpression elicits a potent antitumor efficacy on human colorectal cancer and hepatoma cells both in vitro and in vivo. Cancer gene therapy 12 18617915
2020 VPS53 Suppresses Malignant Properties in Colorectal Cancer by Inducing the Autophagy Signaling Pathway. OncoTargets and therapy 8 33116643
2015 Characterization and functional analysis of a chitin synthase gene (HcCS1) identified from the freshwater pearlmussel Hyriopsis cumingii. Genetics and molecular research : GMR 6 26782579
2008 Potent anti-hepatoma efficacy of HCCS1 via dual tumor-targeting gene-virotherapy strategy. Oncology reports 5 18949398
2006 Transcription of the putative tumor suppressor gene HCCS1 requires binding of ETS-2 to its consensus near the transcription start site. Cell research 5 16953216
2003 Genetic alterations of the HCCS1 gene in Korean hepatocellular carcinoma. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 5 12780520
2018 GZFLW Induces Apoptosis of Ectopic Endometrial Stromal Cells via Promoting VPS53 Protein Stability. Evidence-based complementary and alternative medicine : eCAM 2 30643524
2019 HCCS1 inhibits the stemness of human pancreatic cancer stem-like cells. European review for medical and pharmacological sciences 0 30915757
2012 Expression and clinical significance of HCCS1 in non-small cell lung cancer. Contemporary oncology (Poznan, Poland) 0 23788903
2008 [Tumor-targeting expression of a new tumor suppressor gene HCCS1 and its tumor-selective inhibitory effects on hepatocellular carcinoma]. Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology 0 18510848