Affinage

TRAPPC6A

Trafficking protein particle complex subunit 6A · UniProt O75865

Length
159 aa
Mass
17.6 kDa
Annotated
2026-06-10
22 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRAPPC6A is a conserved core subunit of the TRAPP (transport protein particle) tethering complexes that supports Rab GTPase-dependent vesicle trafficking through the secretory and autophagic pathways (PMID:16262728, PMID:37713627). It binds directly to the TRAPP subunit Bet3/TRAPPC3 through a structurally defined interface and acts as an assembly node: this interaction facilitates further Bet3 protein-protein contacts, including with Bet5, and promotes proper Golgi localization of TRAPP components (PMID:16262728). In yeast, the ortholog Trs33 is required for stable incorporation of accessory subunits and is needed for Golgi-endosomal recycling, Rab GTPase (Ypt31/Ypt1) localization, and Ypt1-mediated recruitment of core TRAPP to the preautophagosomal structure during autophagy (PMID:19220810, PMID:27672095). TRAPPC6A defines a specific surface of the TRAPP core onto which metazoan-specific subunits assemble via TRAPPC2L, with which it interacts directly (PMID:31869332, PMID:32843486). In mammals TRAPPC6A participates equally in both TRAPP II and TRAPP III complexes and its function is conserved enough that human TRAPPC6A complements loss of yeast Trs33 (PMID:37713627, PMID:39273027). Loss of Trappc6a in mouse disrupts melanosome biogenesis, producing hypopigmentation and abnormal melanosomes in the retinal pigmented epithelium (PMID:16697553). Beyond its core trafficking role, an alternatively spliced internal-deletion isoform, TRAPPC6AΔ, binds WWOX; TGF-β1-induced dissociation of this complex triggers Ser35 phosphorylation-dependent polymerization, caspase 3 activation, and Aβ production, and the same isoform binds influenza A M2 protein (via M2 Leu96) to slow its trafficking to the apical plasma membrane and enhance viral replication (PMID:25650666, PMID:27795429).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2005 High

    Established the molecular basis by which TRAPPC6A/Trs33 contributes to TRAPP complex architecture, answering how this small subunit influences complex assembly.

    Evidence 2.2 Å crystal structure of mammalian Bet3-Trs33, in vitro binding assays, and yeast mutagenesis

    PMID:16262728

    Open questions at the time
    • Does not define the full intact TRAPP assembly geometry
    • Functional consequence for Rab activation not directly tested
  2. 2006 Medium

    Linked TRAPPC6A to a specific physiological trafficking output by showing loss of function disrupts melanosome biogenesis in vivo.

    Evidence Spontaneous loss-of-function mouse mutant with melanosome histology and expression analysis

    PMID:16697553

    Open questions at the time
    • Cellular trafficking step disrupted in melanosomes not resolved
    • Which TRAPP isocomplex mediates this is unknown
  3. 2008 Medium

    Demonstrated that human TRAPPC6A associates with Bet3 and partitions among distinct TRAPP isocomplexes, extending the assembly role to human ER-to-Golgi traffic.

    Evidence Tandem affinity purification plus gel filtration in human cells

    PMID:18930054

    Open questions at the time
    • Functional difference between isocomplexes not defined
    • Stoichiometry not established
  4. 2009 Medium

    Placed Trs33 in the pathway by showing it controls accessory subunit incorporation, Rab GTPase localization, and Golgi-endosomal recycling.

    Evidence Yeast deletion analysis, co-immunoprecipitation, and fluorescence microscopy of Ypt31 and Snc1

    PMID:19220810

    Open questions at the time
    • Direct GEF activity contribution not measured
    • Mammalian conservation of Snc1 recycling role untested
  5. 2015 Medium

    Revealed a non-canonical neurodegeneration-linked role for an alternatively spliced isoform interacting with WWOX and driving aggregation cascades.

    Evidence Filter retardation, co-IP dissociation by TGF-β1, siRNA knockdown, caspase assay, and Wwox knockout mouse histology

    PMID:25650666

    Open questions at the time
    • Relationship of TRAPPC6AΔ aggregation to canonical TRAPP trafficking unclear
    • Ser35 kinase not identified
  6. 2016 Medium

    Identified TRAPPC6A/TRAPPC6AΔ as host factors hijacked by influenza M2, defining a role in regulating M2 plasma membrane trafficking.

    Evidence Yeast two-hybrid screen, mutagenesis (M2 Leu96), siRNA knockdown, and recombinant virus trafficking assays in mice

    PMID:27795429

    Open questions at the time
    • Whether TRAPP tethering machinery as a whole is involved is unresolved
    • Mechanism by which trafficking is slowed not defined
  7. 2016 Medium

    Showed Trs33 is required for Ypt1-mediated autophagy and core-TRAPP recruitment to the PAS, extending its role beyond Golgi traffic to autophagy.

    Evidence Yeast double-mutant epistasis and fluorescence microscopy of PAS recruitment with autophagy assays

    PMID:27672095

    Open questions at the time
    • Autophagy role in mammalian TRAPPC6A untested
    • Distinct TRAPP IV complex composition not fully defined
  8. 2018 Low

    Provided initial evidence that TRAPPC6A protein abundance is controlled by proteasomal degradation, relevant to disease-associated mutants.

    Evidence Exome sequencing with wild-type versus mutant cDNA expression and MG132 treatment in HEK293 cells

    PMID:29391579

    Open questions at the time
    • No direct ubiquitination or E3 ligase identified
    • Single expression experiment without endogenous validation
  9. 2019 Medium

    Mapped TRAPPC6A as the interface ('Trs33 side') onto which metazoan-specific subunits are recruited via TRAPPC2L.

    Evidence Size-fractionation chromatography, MS-based purification, and negative-stain EM in Aspergillus nidulans

    PMID:31869332

    Open questions at the time
    • High-resolution structure of the metazoan assembly absent
    • Direct human reconstitution not performed
  10. 2020 Medium

    Confirmed a direct TRAPPC6A–TRAPPC2L interaction and showed a pathogenic variant disrupts assembly and Golgi trafficking, cementing TRAPPC6A as a core binding partner.

    Evidence Yeast two-hybrid, in vitro binding, size exclusion chromatography, and trafficking assays in patient fibroblasts

    PMID:32843486

    Open questions at the time
    • Variant effect on TRAPPC6A itself not measured
    • In vivo disease mechanism beyond fibroblasts unresolved
  11. 2024 Medium

    Defined the isocomplex distribution of TRAPPC6A, showing it participates equally in TRAPP II and TRAPP III, distinguishing it from its paralog.

    Evidence Reciprocal co-immunoprecipitation from patient-derived fibroblasts comparing TRAPPC6A and TRAPPC6B

    PMID:37713627

    Open questions at the time
    • Functional consequence of equal partitioning unclear
    • Quantitative stoichiometry within each complex not measured
  12. 2024 Low

    Demonstrated cross-species conservation of TRAPPC6A core function via humanized yeast complementation.

    Evidence CRISPR/Cas9 humanized yeast model replacing Trs33p with human TRAPPC6A

    PMID:39273027

    Open questions at the time
    • Single complementation readout
    • No mechanistic dissection of TRAPPC6A-specific functions

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the canonical TRAPP tethering role of TRAPPC6A mechanistically relates to its isoform-specific roles in neurodegeneration, viral trafficking, and melanosome biogenesis remains unresolved.
  • No unified model connecting full-length and TRAPPC6AΔ functions
  • Direct Rab GEF mechanism for mammalian TRAPPC6A not established
  • Structure of intact human TRAPP II/III with TRAPPC6A lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3
Localization
GO:0005794 Golgi apparatus 2 GO:0005829 cytosol 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-9612973 Autophagy 1
Partners
TRAPPC2LTRAPPC3WWOX
Complex memberships
TRAPP IITRAPP IIITRAPP IV

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 TRAPPC6A (Trs33p) directly binds TRAPP subunit Bet3p; a mammalian Bet3-Trs33 complex was crystallized and the structure solved to 2.2 Å resolution, revealing similar overall folds despite low sequence identity. In vitro experiments showed that Bet3p binding to Trs33p facilitates the interaction between Bet3p and another TRAPP subunit Bet5p. Mutational analysis indicated that Trs33p facilitates other Bet3p protein-protein interactions, and Trs33p can increase the Golgi-localized pool of a mutated Bet3 protein normally found in the cytosol. Crystal structure (2.2 Å), in vitro binding assays, yeast mutational analysis Traffic (Copenhagen, Denmark) High 16262728
2006 Loss-of-function mutation in mouse Trappc6a (caused by retroviral integration that markedly diminishes expression) results in mosaic hypopigmentation and abnormal melanosomes in the retinal pigmented epithelium, implicating TRAPPC6A in vesicle trafficking during melanosome biogenesis. Spontaneous mouse mutant characterization: genetic mapping, retroviral insertion identification, expression analysis, histology of melanosomes Genomics Medium 16697553
2008 Human TRAPPC6A (one of two paralogs of Trs33) associates with Bet3 in human cells and participates in at least one of two distinct TRAPP isocomplexes that may exert different functions in ER-to-Golgi traffic. Tandem affinity purification (TAP) followed by interaction studies and gel filtration analysis FEBS letters Medium 18930054
2009 Yeast Trs33 (ortholog of TRAPPC6A) is required for Golgi-endosomal recycling of Snc1. Mutation of TRS33 perturbs the association of Trs65 with the rest of the TRAPP complex and alters the localization of the Rab GTPase Ypt31. Tca17 interacts with the TRAPP complex in a Trs33- and Trs65-dependent manner, and together these subunits promote TRAPP complex assembly and/or stability. Genetic deletion analysis, co-immunoprecipitation, fluorescence microscopy of Rab GTPase localization and Snc1 recycling Traffic (Copenhagen, Denmark) Medium 19220810
2015 An N-terminal internal-deletion isoform of TRAPPC6A, TRAPPC6AΔ (TPC6AΔ), derived from alternative splicing, forms aggregates/plaques in the extracellular matrix of the brain. TGF-β1 induces dissociation of the TRAPPC6AΔ–WWOX complex; free TRAPPC6AΔ then undergoes Ser35 phosphorylation-dependent polymerization, induces caspase 3 activation, and promotes Aβ production. Knockdown of WWOX by siRNA dramatically increases TRAPPC6AΔ aggregation. Filter retardation assay, co-immunoprecipitation (ectopic complex dissociation by TGF-β1), siRNA knockdown, caspase activity assay, Wwox knockout mouse model histology Oncotarget Medium 25650666
2016 TRAPPC6A and its isoform TRAPPC6AΔ interact with influenza A virus M2 protein; the leucine residue at position 96 of M2 is critical for this interaction. TRAPPC6AΔ slows M2 trafficking to the apical plasma membrane, thereby positively modulating viral replication in vitro and virulence in mice. Yeast two-hybrid screen, truncation/mutation analyses, siRNA knockdown of endogenous TRAPPC6AΔ, recombinant virus unable to interact with TRAPPC6A/TRAPPC6AΔ, M2 trafficking assay Journal of virology Medium 27795429
2016 Yeast Trs33 (ortholog of TRAPPC6A) assembles into a distinct TRAPP complex (TRAPP IV) separate from TRAPP I. In the absence of Trs85 (TRAPP III subunit), Trs33 is required for Ypt1-mediated autophagy and for recruitment of core-TRAPP and Ypt1 to the preautophagosomal structure (PAS). Yeast genetics (double mutant analysis, deletion strains), fluorescence microscopy of PAS recruitment, autophagy assays Genetics Medium 27672095
2018 A missense mutation in TRAPPC6A leads to build-up of the mutant protein in HEK293 cells, while wild-type TRAPPC6A is normally unstable and degraded by the proteasome (stabilized by MG132 treatment), indicating TRAPPC6A protein stability is regulated by the proteasome. Exome sequencing, expression of wild-type vs. mutant cDNA in HEK293 cells, proteasome inhibitor (MG132) treatment Scientific reports Low 29391579
2019 In Aspergillus nidulans (fungal ortholog system), the TRAPPC2L subunit binds to the 'Trs33 side' of the TRAPP core and recruits additional metazoan-specific subunits (TRAPPC11, TRAPPC12, TRAPPC13), revealing that TRAPPC6A/Trs33 defines a specific interface for TRAPP complex assembly. Size-fractionation chromatography, single-step purification coupled to mass spectrometry, negative-stain electron microscopy PLoS genetics Medium 31869332
2020 TRAPPC2L directly interacts with TRAPPC6A as demonstrated by yeast two-hybrid assay and in vitro binding; a pathogenic TRAPPC2L p.(Ala2Gly) variant disrupts this interaction, affects TRAPP complex assembly by size exclusion chromatography, and leads to membrane trafficking delays into and out of the Golgi. This positions TRAPPC6A as a core TRAPP binding partner for TRAPPC2L. Yeast two-hybrid assay, in vitro binding assay, size exclusion chromatography, membrane trafficking assays in patient fibroblasts Journal of medical genetics Medium 32843486
2024 Co-immunoprecipitation experiments showed that TRAPPC6A co-precipitates equally with TRAPP II and TRAPP III complexes, while the paralog TRAPPC6B co-precipitates significantly more with TRAPP II, indicating that TRAPPC6A participates in both TRAPP II and TRAPP III complexes without preferential enrichment in either. Co-immunoprecipitation from patient-derived fibroblasts and cell lines Brain : a journal of neurology Medium 37713627
2024 Human TRAPPC6A functionally replaces its yeast ortholog Trs33p in a humanized yeast model (CRISPR/Cas9 replacement), demonstrating conservation of core TRAPP function across species. CRISPR/Cas9-based humanized yeast model complementation assay Cells Low 39273027

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 High-resolution mapping, cloning and molecular characterization of the Pi-k ( h ) gene of rice, which confers resistance to Magnaporthe grisea. Molecular genetics and genomics : MGG 87 16228246
2009 Identification of the novel TRAPP associated protein Tca17. Traffic (Copenhagen, Denmark) 44 19220810
2016 Host Cellular Protein TRAPPC6AΔ Interacts with Influenza A Virus M2 Protein and Regulates Viral Propagation by Modulating M2 Trafficking. Journal of virology 38 27795429
2015 Trafficking protein particle complex 6A delta (TRAPPC6AΔ) is an extracellular plaque-forming protein in the brain. Oncotarget 37 25650666
2017 Zfra restores memory deficits in Alzheimer's disease triple-transgenic mice by blocking aggregation of TRAPPC6AΔ, SH3GLB2, tau, and amyloid β, and inflammatory NF-κB activation. Alzheimer's & dementia (New York, N. Y.) 34 29067327
2018 A missense mutation in TRAPPC6A leads to build-up of the protein, in patients with a neurodevelopmental syndrome and dysmorphic features. Scientific reports 28 29391579
2016 Trs33-Containing TRAPP IV: A Novel Autophagy-Specific Ypt1 GEF. Genetics 26 27672095
2006 A mouse TRAPP-related protein is involved in pigmentation. Genomics 26 16697553
2005 Biochemical and crystallographic studies reveal a specific interaction between TRAPP subunits Trs33p and Bet3p. Traffic (Copenhagen, Denmark) 25 16262728
2019 Characterization of Aspergillus nidulans TRAPPs uncovers unprecedented similarities between fungi and metazoans and reveals the modular assembly of TRAPPII. PLoS genetics 23 31869332
2008 Distinct isocomplexes of the TRAPP trafficking factor coexist inside human cells. FEBS letters 21 18930054
2021 WWOX and Its Binding Proteins in Neurodegeneration. Cells 18 34359949
2012 Signal transducer and activator of transcription 2 (STAT2) metabolism coupling postmitotic outgrowth to visual and sound perception network in human left cerebrum by biocomputation. Journal of molecular neuroscience : MN 18 22219046
2021 DNA methylation at birth potentially mediates the association between prenatal lead (Pb) exposure and infant neurodevelopmental outcomes. Environmental epigenetics 17 34141453
2020 Association of blood-based transcriptional risk scores with biomarkers for Alzheimer disease. Neurology. Genetics 17 33134515
2020 A novel homozygous variant in TRAPPC2L results in a neurodevelopmental disorder and disrupts TRAPP complex function. Journal of medical genetics 14 32843486
2024 TRAPPC6B biallelic variants cause a neurodevelopmental disorder with TRAPP II and trafficking disruptions. Brain : a journal of neurology 5 37713627
2016 Induction of Genes Expressed in Endothelial Cells of the Corpus Callosum in the Chronic Cerebral Hypoperfusion Rat Model. Pathobiology : journal of immunopathology, molecular and cellular biology 5 27458816
2012 Functional roles of YPT31 and YPT32 in clotrimazole resistance of Saccharomyces cerevisiae through effects on vacuoles and ATP-binding cassette transporter(s). Journal of bioscience and bioengineering 5 22999853
2024 A Humanized Yeast Model for Studying TRAPP Complex Mutations; Proof-of-Concept Using Variants from an Individual with a TRAPPC1-Associated Neurodevelopmental Syndrome. Cells 4 39273027
2022 Zfra Inhibits the TRAPPC6AΔ-Initiated Pathway of Neurodegeneration. International journal of molecular sciences 3 36498839
2025 Multi-task learning identifies shared genetic risk for late-onset epilepsy and alzheimer's disease. Scientific reports 0 41390778

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