Affinage

VPS53

Vacuolar protein sorting-associated protein 53 homolog · UniProt Q5VIR6

Length
832 aa
Mass
94.4 kDa
Annotated
2026-06-11
17 papers in source corpus 5 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VPS53 is a subunit of the Golgi-associated retrograde protein (GARP) tethering complex that mediates retrograde transport of endosome-derived vesicles to the trans-Golgi network (PMID:24577744). Its C-terminal domain adopts two tandem alpha-helical bundles bearing a conserved surface patch; mutagenesis of this patch disrupts membrane traffic, identifying the region as the functional element for vesicle recognition in endosome-to-TGN retrograde transport (PMID:20660722). This fold is shared with subunits of the Dsl1, COG, and exocyst tethering complexes, placing GARP within a common evolutionary family of membrane-tethering machines (PMID:20660722). In human cells, loss-of-function mutations affecting the VPS53 C-terminal domain cause accumulation of swollen CD63-positive vesicular bodies, confirming that VPS53 is required for retrograde endosome-to-Golgi recycling (PMID:24577744). Biallelic VPS53 mutations cause progressive neurological disease, including complicated hereditary spastic paraparesis (PMID:24577744, PMID:31418091).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2010 High

    Established the structural basis for how VPS53 contributes to vesicle tethering, answering which part of the protein performs the recognition function and revealing its evolutionary relationship to other tethering complexes.

    Evidence X-ray crystallography of the Vps53 C-terminal fragment at 2.9 Å with site-directed mutagenesis and membrane traffic assay

    PMID:20660722

    Open questions at the time
    • Structure covers only the C-terminal fragment, not the full GARP assembly
    • Identity of the recognized vesicle component/SNARE not resolved
    • How the conserved patch engages incoming vesicles mechanistically not shown
  2. 2014 Medium

    Connected VPS53 GARP function to human cell biology and disease, showing that C-terminal mutations disrupt retrograde recycling and produce a measurable endosomal phenotype in patient cells.

    Evidence Whole exome sequencing, linkage analysis, and CD63 immunofluorescence in patient-derived fibroblasts

    PMID:24577744

    Open questions at the time
    • Cargo whose missorting drives the cellular phenotype not identified
    • Single-lab patient-cell observation without biochemical reconstitution
    • Link between vesicle accumulation and neurological pathology not mechanistically traced
  3. 2019 Low

    Extended the genetic spectrum by linking a homozygous VPS53 missense variant to complicated hereditary spastic paraparesis, framing GARP dysfunction in a lysosomal lipid-homeostasis context.

    Evidence Whole exome sequencing with family-based genetic analysis

    PMID:31418091

    Open questions at the time
    • Genetic identification only; no biochemical functional assay performed
    • Proposed role in cholesterol/sphingolipid transport not directly tested for this variant
    • Causal mechanism linking variant to neurodegeneration unestablished
  4. 2020 Low

    Raised a possible role for VPS53 upstream of autophagy in cancer cells, distinct from its canonical trafficking function.

    Evidence Overexpression in colorectal cancer cells with autophagy marker Western blotting, proliferation/migration/invasion assays, and autophagy inhibitor rescue

    PMID:33116643

    Open questions at the time
    • No mechanistic link between GARP/retrograde function and autophagy induction established
    • Overexpression-based; physiological relevance unclear
    • Single-lab finding without independent confirmation
  5. 2018 Low

    Indicated that VPS53 abundance is controlled post-translationally, hinting at regulation of the protein independent of transcription.

    Evidence iTRAQ proteomics, LC-MS/MS, and Western blotting in human endometrial stromal cells

    PMID:30643524

    Open questions at the time
    • Mechanism of protein stabilization not elucidated
    • Single-lab proteomic observation
    • Functional consequence for GARP trafficking not assessed

Open questions

Synthesis pass · forward-looking unresolved questions
  • The specific vesicular cargo recognized by the VPS53 conserved surface patch and how GARP-dependent retrograde defects translate into neurodegeneration remain undefined.
  • No identified cargo or SNARE partner for the tethering reaction
  • No full-length GARP complex structure
  • Causal chain from trafficking defect to neuronal pathology not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3
Localization
GO:0005768 endosome 2 GO:0005794 Golgi apparatus 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 3
Complex memberships
GARP complex

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 Crystal structure of the C-terminal fragment of Vps53 (at 2.9 Å resolution) revealed two alpha-helical bundles arranged in tandem with a highly conserved surface patch. Mutagenesis of this surface patch caused defects in membrane traffic, identifying this region as functionally critical for vesicle recognition in endosome-to-TGN retrograde transport. X-ray crystallography (2.9 Å) combined with site-directed mutagenesis and membrane traffic functional assay Proceedings of the National Academy of Sciences of the United States of America High 20660722
2010 The fold of the Vps53 C-terminal domain is structurally reminiscent of subunits from three other tethering complexes (Dsl1, conserved oligomeric Golgi, and the exocyst), indicating that GARP belongs to the same evolutionary family of membrane-tethering complexes. Structural comparison via X-ray crystallography Proceedings of the National Academy of Sciences of the United States of America High 20660722
2014 Loss-of-function compound heterozygous mutations in VPS53 (c.2084A>G and c.1556+5G>A) affecting its C-terminal domain cause abnormal accumulation of swollen CD63-positive vesicular bodies (likely intermediate recycling/late endosomes) in patient fibroblasts, establishing VPS53 as essential for retrograde endosome-to-Golgi vesicle recycling in human cells. Immunofluorescence microscopy of patient fibroblasts with CD63 marker; whole exome sequencing and linkage analysis Journal of medical genetics Medium 24577744
2014 VPS53 functions as a subunit of the Golgi-associated retrograde protein (GARP) complex, which mediates retrograde transport of endocytic vesicles to the trans-Golgi network; the C-terminal domain of VPS53 is critical for this function. Genetic mapping, whole exome sequencing, and immunofluorescence microscopy in patient-derived fibroblasts Journal of medical genetics Medium 24577744
2019 A homozygous VPS53 missense variant (c.2084A>G, p.Gln695Arg) was identified as causative in complicated hereditary spastic paraparesis, placing VPS53/GARP function in intracellular cholesterol transport and sphingolipid homeostasis in lysosomes as relevant to neurodegeneration. Whole exome sequencing with family-based genetic analysis Neurogenetics Low 31418091
2020 Overexpression of VPS53 in colorectal cancer cells upregulated Beclin 1 and LC3B-II and induced autophagy; pharmacological inhibition of autophagy attenuated the VPS53-mediated suppression of cancer cell proliferation, migration, and invasion, placing VPS53 upstream of the autophagy pathway in CRC cells. Overexpression with CCK-8, flow cytometry, transwell assay, electron microscopy, and Western blotting; autophagy inhibitor rescue experiment OncoTargets and therapy Low 33116643
2018 Treatment with GZFLW increased VPS53 protein stability (not mRNA level) in endometrial stromal cells, suggesting VPS53 is subject to post-translational regulation of protein stability, and elevated VPS53 promoted apoptosis in these cells. iTRAQ proteomics, LC-MS/MS, and Western blotting in human endometrial stromal cells 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 72 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 33 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 17 11857354
2019 VPS53 gene is associated with a new phenotype of complicated hereditary spastic paraparesis. Neurogenetics 14 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

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