{"gene":"TRAPPC6A","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2005,"finding":"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.","method":"Crystal structure (2.2 Å), in vitro binding assays, yeast mutational analysis","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure solved plus in vitro reconstitution plus mutagenesis, all in single rigorous study","pmids":["16262728"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Spontaneous mouse mutant characterization: genetic mapping, retroviral insertion identification, expression analysis, histology of melanosomes","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function mouse model with defined cellular phenotype (melanosome biogenesis defect), single lab but multiple complementary methods","pmids":["16697553"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Tandem affinity purification (TAP) followed by interaction studies and gel filtration analysis","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TAP purification plus gel filtration, single lab, two orthogonal methods","pmids":["18930054"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Genetic deletion analysis, co-immunoprecipitation, fluorescence microscopy of Rab GTPase localization and Snc1 recycling","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic and cell biological methods in single lab establishing pathway position","pmids":["19220810"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Filter retardation assay, co-immunoprecipitation (ectopic complex dissociation by TGF-β1), siRNA knockdown, caspase activity assay, Wwox knockout mouse model histology","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple orthogonal in vitro and in vivo methods in single lab; mechanistic detail on Ser35 phosphorylation and WWOX interaction established","pmids":["25650666"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Yeast two-hybrid screen, truncation/mutation analyses, siRNA knockdown of endogenous TRAPPC6AΔ, recombinant virus unable to interact with TRAPPC6A/TRAPPC6AΔ, M2 trafficking assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Y2H plus mutagenesis plus functional rescue with recombinant virus, single lab, multiple orthogonal methods","pmids":["27795429"],"is_preprint":false},{"year":2016,"finding":"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).","method":"Yeast genetics (double mutant analysis, deletion strains), fluorescence microscopy of PAS recruitment, autophagy assays","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis combined with localization microscopy, single lab, multiple methods","pmids":["27672095"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Exome sequencing, expression of wild-type vs. mutant cDNA in HEK293 cells, proteasome inhibitor (MG132) treatment","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single expression experiment with proteasome inhibitor; no direct ubiquitination or E3 ligase identification","pmids":["29391579"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Size-fractionation chromatography, single-step purification coupled to mass spectrometry, negative-stain electron microscopy","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — structural EM plus MS-based complex purification, multiple orthogonal methods, single lab","pmids":["31869332"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Yeast two-hybrid assay, in vitro binding assay, size exclusion chromatography, membrane trafficking assays in patient fibroblasts","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Y2H plus in vitro binding plus functional trafficking assay, single lab with multiple orthogonal methods","pmids":["32843486"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-immunoprecipitation from patient-derived fibroblasts and cell lines","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with comparison to paralog, single lab, direct experimental result","pmids":["37713627"],"is_preprint":false},{"year":2024,"finding":"Human TRAPPC6A functionally replaces its yeast ortholog Trs33p in a humanized yeast model (CRISPR/Cas9 replacement), demonstrating conservation of core TRAPP function across species.","method":"CRISPR/Cas9-based humanized yeast model complementation assay","journal":"Cells","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single complementation result, proof-of-concept study, no deeper mechanistic dissection of TRAPPC6A itself","pmids":["39273027"],"is_preprint":false}],"current_model":"TRAPPC6A is a conserved core subunit of TRAPP tethering complexes (participating in both TRAPP II and TRAPP III) that directly binds Bet3/TRAPPC3 via a structurally characterized interface to facilitate TRAPP complex assembly and Rab GTPase-mediated vesicle trafficking from the ER through the Golgi; in mammals it additionally modulates post-Golgi trafficking events including melanosome biogenesis and, via an alternatively-spliced isoform (TRAPPC6AΔ), interacts with WWOX and influences protein aggregation cascades linked to neurodegeneration, as well as regulating influenza M2 protein trafficking to the plasma membrane."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2005,"claim":"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","pmids":["16262728"],"confidence":"High","gaps":["Does not define the full intact TRAPP assembly geometry","Functional consequence for Rab activation not directly tested"]},{"year":2006,"claim":"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","pmids":["16697553"],"confidence":"Medium","gaps":["Cellular trafficking step disrupted in melanosomes not resolved","Which TRAPP isocomplex mediates this is unknown"]},{"year":2008,"claim":"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","pmids":["18930054"],"confidence":"Medium","gaps":["Functional difference between isocomplexes not defined","Stoichiometry not established"]},{"year":2009,"claim":"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","pmids":["19220810"],"confidence":"Medium","gaps":["Direct GEF activity contribution not measured","Mammalian conservation of Snc1 recycling role untested"]},{"year":2015,"claim":"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","pmids":["25650666"],"confidence":"Medium","gaps":["Relationship of TRAPPC6AΔ aggregation to canonical TRAPP trafficking unclear","Ser35 kinase not identified"]},{"year":2016,"claim":"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","pmids":["27795429"],"confidence":"Medium","gaps":["Whether TRAPP tethering machinery as a whole is involved is unresolved","Mechanism by which trafficking is slowed not defined"]},{"year":2016,"claim":"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","pmids":["27672095"],"confidence":"Medium","gaps":["Autophagy role in mammalian TRAPPC6A untested","Distinct TRAPP IV complex composition not fully defined"]},{"year":2018,"claim":"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","pmids":["29391579"],"confidence":"Low","gaps":["No direct ubiquitination or E3 ligase identified","Single expression experiment without endogenous validation"]},{"year":2019,"claim":"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","pmids":["31869332"],"confidence":"Medium","gaps":["High-resolution structure of the metazoan assembly absent","Direct human reconstitution not performed"]},{"year":2020,"claim":"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","pmids":["32843486"],"confidence":"Medium","gaps":["Variant effect on TRAPPC6A itself not measured","In vivo disease mechanism beyond fibroblasts unresolved"]},{"year":2024,"claim":"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","pmids":["37713627"],"confidence":"Medium","gaps":["Functional consequence of equal partitioning unclear","Quantitative stoichiometry within each complex not measured"]},{"year":2024,"claim":"Demonstrated cross-species conservation of TRAPPC6A core function via humanized yeast complementation.","evidence":"CRISPR/Cas9 humanized yeast model replacing Trs33p with human TRAPPC6A","pmids":["39273027"],"confidence":"Low","gaps":["Single complementation readout","No mechanistic dissection of TRAPPC6A-specific functions"]},{"year":null,"claim":"How the canonical TRAPP tethering role of TRAPPC6A mechanistically relates to its isoform-specific roles in neurodegeneration, viral trafficking, and melanosome biogenesis remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,8,9]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,3,9]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6]}],"complexes":["TRAPP II","TRAPP III","TRAPP IV"],"partners":["TRAPPC3","TRAPPC2L","WWOX"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75865","full_name":"Trafficking protein particle complex subunit 6A","aliases":[],"length_aa":159,"mass_kda":17.6,"function":"May play a role in vesicular transport during the biogenesis of melanosomes","subcellular_location":"Golgi apparatus, cis-Golgi network; Endoplasmic reticulum","url":"https://www.uniprot.org/uniprotkb/O75865/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRAPPC6A","classification":"Not Classified","n_dependent_lines":43,"n_total_lines":1208,"dependency_fraction":0.03559602649006623},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TRAPPC6A","total_profiled":1310},"omim":[{"mim_id":"610397","title":"TRAFFICKING PROTEIN PARTICLE COMPLEX, SUBUNIT 6B; TRAPPC6B","url":"https://www.omim.org/entry/610397"},{"mim_id":"610396","title":"TRAFFICKING PROTEIN PARTICLE COMPLEX, SUBUNIT 6A; TRAPPC6A","url":"https://www.omim.org/entry/610396"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TRAPPC6A"},"hgnc":{"alias_symbol":["TRS33","MGC2650","HSPC289"],"prev_symbol":[]},"alphafold":{"accession":"O75865","domains":[{"cath_id":"3.30.1380.20","chopping":"5-156","consensus_level":"high","plddt":91.3395,"start":5,"end":156}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75865","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75865-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75865-F1-predicted_aligned_error_v6.png","plddt_mean":90.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRAPPC6A","jax_strain_url":"https://www.jax.org/strain/search?query=TRAPPC6A"},"sequence":{"accession":"O75865","fasta_url":"https://rest.uniprot.org/uniprotkb/O75865.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75865/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75865"}},"corpus_meta":[{"pmid":"16228246","id":"PMC_16228246","title":"High-resolution mapping, cloning and molecular characterization of the Pi-k ( h ) gene of rice, which confers resistance to Magnaporthe grisea.","date":"2005","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/16228246","citation_count":87,"is_preprint":false},{"pmid":"19220810","id":"PMC_19220810","title":"Identification of the novel TRAPP associated protein Tca17.","date":"2009","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/19220810","citation_count":44,"is_preprint":false},{"pmid":"27795429","id":"PMC_27795429","title":"Host Cellular Protein TRAPPC6AΔ Interacts with Influenza A Virus M2 Protein and Regulates Viral Propagation by Modulating M2 Trafficking.","date":"2016","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/27795429","citation_count":38,"is_preprint":false},{"pmid":"25650666","id":"PMC_25650666","title":"Trafficking protein particle complex 6A delta (TRAPPC6AΔ) is an extracellular plaque-forming protein in the brain.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/25650666","citation_count":37,"is_preprint":false},{"pmid":"29067327","id":"PMC_29067327","title":"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.","date":"2017","source":"Alzheimer's & dementia (New York, N. Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/29067327","citation_count":34,"is_preprint":false},{"pmid":"29391579","id":"PMC_29391579","title":"A missense mutation in TRAPPC6A leads to build-up of the protein, in patients with a neurodevelopmental syndrome and dysmorphic features.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29391579","citation_count":28,"is_preprint":false},{"pmid":"27672095","id":"PMC_27672095","title":"Trs33-Containing TRAPP IV: A Novel Autophagy-Specific Ypt1 GEF.","date":"2016","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27672095","citation_count":26,"is_preprint":false},{"pmid":"16697553","id":"PMC_16697553","title":"A mouse TRAPP-related protein is involved in pigmentation.","date":"2006","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/16697553","citation_count":26,"is_preprint":false},{"pmid":"16262728","id":"PMC_16262728","title":"Biochemical and crystallographic studies reveal a specific interaction between TRAPP subunits Trs33p and Bet3p.","date":"2005","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/16262728","citation_count":25,"is_preprint":false},{"pmid":"31869332","id":"PMC_31869332","title":"Characterization of Aspergillus nidulans TRAPPs uncovers unprecedented similarities between fungi and metazoans and reveals the modular assembly of TRAPPII.","date":"2019","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31869332","citation_count":23,"is_preprint":false},{"pmid":"18930054","id":"PMC_18930054","title":"Distinct isocomplexes of the TRAPP trafficking factor coexist inside human cells.","date":"2008","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/18930054","citation_count":21,"is_preprint":false},{"pmid":"34359949","id":"PMC_34359949","title":"WWOX and Its Binding Proteins in Neurodegeneration.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34359949","citation_count":18,"is_preprint":false},{"pmid":"22219046","id":"PMC_22219046","title":"Signal transducer and activator of transcription 2 (STAT2) metabolism coupling postmitotic outgrowth to visual and sound perception network in human left cerebrum by biocomputation.","date":"2012","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/22219046","citation_count":18,"is_preprint":false},{"pmid":"33134515","id":"PMC_33134515","title":"Association of blood-based transcriptional risk scores with biomarkers for Alzheimer disease.","date":"2020","source":"Neurology. 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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.\",\n      \"method\": \"Crystal structure (2.2 Å), in vitro binding assays, yeast mutational analysis\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure solved plus in vitro reconstitution plus mutagenesis, all in single rigorous study\",\n      \"pmids\": [\"16262728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Spontaneous mouse mutant characterization: genetic mapping, retroviral insertion identification, expression analysis, histology of melanosomes\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function mouse model with defined cellular phenotype (melanosome biogenesis defect), single lab but multiple complementary methods\",\n      \"pmids\": [\"16697553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Tandem affinity purification (TAP) followed by interaction studies and gel filtration analysis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TAP purification plus gel filtration, single lab, two orthogonal methods\",\n      \"pmids\": [\"18930054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic deletion analysis, co-immunoprecipitation, fluorescence microscopy of Rab GTPase localization and Snc1 recycling\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic and cell biological methods in single lab establishing pathway position\",\n      \"pmids\": [\"19220810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Filter retardation assay, co-immunoprecipitation (ectopic complex dissociation by TGF-β1), siRNA knockdown, caspase activity assay, Wwox knockout mouse model histology\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple orthogonal in vitro and in vivo methods in single lab; mechanistic detail on Ser35 phosphorylation and WWOX interaction established\",\n      \"pmids\": [\"25650666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid screen, truncation/mutation analyses, siRNA knockdown of endogenous TRAPPC6AΔ, recombinant virus unable to interact with TRAPPC6A/TRAPPC6AΔ, M2 trafficking assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Y2H plus mutagenesis plus functional rescue with recombinant virus, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"27795429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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).\",\n      \"method\": \"Yeast genetics (double mutant analysis, deletion strains), fluorescence microscopy of PAS recruitment, autophagy assays\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis combined with localization microscopy, single lab, multiple methods\",\n      \"pmids\": [\"27672095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Exome sequencing, expression of wild-type vs. mutant cDNA in HEK293 cells, proteasome inhibitor (MG132) treatment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single expression experiment with proteasome inhibitor; no direct ubiquitination or E3 ligase identification\",\n      \"pmids\": [\"29391579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Size-fractionation chromatography, single-step purification coupled to mass spectrometry, negative-stain electron microscopy\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — structural EM plus MS-based complex purification, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"31869332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid assay, in vitro binding assay, size exclusion chromatography, membrane trafficking assays in patient fibroblasts\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Y2H plus in vitro binding plus functional trafficking assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32843486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation from patient-derived fibroblasts and cell lines\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with comparison to paralog, single lab, direct experimental result\",\n      \"pmids\": [\"37713627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Human TRAPPC6A functionally replaces its yeast ortholog Trs33p in a humanized yeast model (CRISPR/Cas9 replacement), demonstrating conservation of core TRAPP function across species.\",\n      \"method\": \"CRISPR/Cas9-based humanized yeast model complementation assay\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single complementation result, proof-of-concept study, no deeper mechanistic dissection of TRAPPC6A itself\",\n      \"pmids\": [\"39273027\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRAPPC6A is a conserved core subunit of TRAPP tethering complexes (participating in both TRAPP II and TRAPP III) that directly binds Bet3/TRAPPC3 via a structurally characterized interface to facilitate TRAPP complex assembly and Rab GTPase-mediated vesicle trafficking from the ER through the Golgi; in mammals it additionally modulates post-Golgi trafficking events including melanosome biogenesis and, via an alternatively-spliced isoform (TRAPPC6AΔ), interacts with WWOX and influences protein aggregation cascades linked to neurodegeneration, as well as regulating influenza M2 protein trafficking to the plasma membrane.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #10]. 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 [#0]. 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 [#3, #6]. TRAPPC6A defines a specific surface of the TRAPP core onto which metazoan-specific subunits assemble via TRAPPC2L, with which it interacts directly [#8, #9]. 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 [#10, #11]. Loss of Trappc6a in mouse disrupts melanosome biogenesis, producing hypopigmentation and abnormal melanosomes in the retinal pigmented epithelium [#1]. Beyond its core trafficking role, an alternatively spliced internal-deletion isoform, TRAPPC6A\\u0394, binds WWOX; TGF-\\u03b21-induced dissociation of this complex triggers Ser35 phosphorylation-dependent polymerization, caspase 3 activation, and A\\u03b2 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 [#4, #5].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established the molecular basis by which TRAPPC6A/Trs33 contributes to TRAPP complex architecture, answering how this small subunit influences complex assembly.\",\n      \"evidence\": \"2.2 \\u00c5 crystal structure of mammalian Bet3-Trs33, in vitro binding assays, and yeast mutagenesis\",\n      \"pmids\": [\"16262728\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the full intact TRAPP assembly geometry\", \"Functional consequence for Rab activation not directly tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Linked TRAPPC6A to a specific physiological trafficking output by showing loss of function disrupts melanosome biogenesis in vivo.\",\n      \"evidence\": \"Spontaneous loss-of-function mouse mutant with melanosome histology and expression analysis\",\n      \"pmids\": [\"16697553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular trafficking step disrupted in melanosomes not resolved\", \"Which TRAPP isocomplex mediates this is unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that human TRAPPC6A associates with Bet3 and partitions among distinct TRAPP isocomplexes, extending the assembly role to human ER-to-Golgi traffic.\",\n      \"evidence\": \"Tandem affinity purification plus gel filtration in human cells\",\n      \"pmids\": [\"18930054\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional difference between isocomplexes not defined\", \"Stoichiometry not established\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placed Trs33 in the pathway by showing it controls accessory subunit incorporation, Rab GTPase localization, and Golgi-endosomal recycling.\",\n      \"evidence\": \"Yeast deletion analysis, co-immunoprecipitation, and fluorescence microscopy of Ypt31 and Snc1\",\n      \"pmids\": [\"19220810\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct GEF activity contribution not measured\", \"Mammalian conservation of Snc1 recycling role untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed a non-canonical neurodegeneration-linked role for an alternatively spliced isoform interacting with WWOX and driving aggregation cascades.\",\n      \"evidence\": \"Filter retardation, co-IP dissociation by TGF-\\u03b21, siRNA knockdown, caspase assay, and Wwox knockout mouse histology\",\n      \"pmids\": [\"25650666\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship of TRAPPC6A\\u0394 aggregation to canonical TRAPP trafficking unclear\", \"Ser35 kinase not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified TRAPPC6A/TRAPPC6A\\u0394 as host factors hijacked by influenza M2, defining a role in regulating M2 plasma membrane trafficking.\",\n      \"evidence\": \"Yeast two-hybrid screen, mutagenesis (M2 Leu96), siRNA knockdown, and recombinant virus trafficking assays in mice\",\n      \"pmids\": [\"27795429\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TRAPP tethering machinery as a whole is involved is unresolved\", \"Mechanism by which trafficking is slowed not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed Trs33 is required for Ypt1-mediated autophagy and core-TRAPP recruitment to the PAS, extending its role beyond Golgi traffic to autophagy.\",\n      \"evidence\": \"Yeast double-mutant epistasis and fluorescence microscopy of PAS recruitment with autophagy assays\",\n      \"pmids\": [\"27672095\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Autophagy role in mammalian TRAPPC6A untested\", \"Distinct TRAPP IV complex composition not fully defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided initial evidence that TRAPPC6A protein abundance is controlled by proteasomal degradation, relevant to disease-associated mutants.\",\n      \"evidence\": \"Exome sequencing with wild-type versus mutant cDNA expression and MG132 treatment in HEK293 cells\",\n      \"pmids\": [\"29391579\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct ubiquitination or E3 ligase identified\", \"Single expression experiment without endogenous validation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mapped TRAPPC6A as the interface ('Trs33 side') onto which metazoan-specific subunits are recruited via TRAPPC2L.\",\n      \"evidence\": \"Size-fractionation chromatography, MS-based purification, and negative-stain EM in Aspergillus nidulans\",\n      \"pmids\": [\"31869332\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"High-resolution structure of the metazoan assembly absent\", \"Direct human reconstitution not performed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Confirmed a direct TRAPPC6A\\u2013TRAPPC2L interaction and showed a pathogenic variant disrupts assembly and Golgi trafficking, cementing TRAPPC6A as a core binding partner.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, size exclusion chromatography, and trafficking assays in patient fibroblasts\",\n      \"pmids\": [\"32843486\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Variant effect on TRAPPC6A itself not measured\", \"In vivo disease mechanism beyond fibroblasts unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the isocomplex distribution of TRAPPC6A, showing it participates equally in TRAPP II and TRAPP III, distinguishing it from its paralog.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation from patient-derived fibroblasts comparing TRAPPC6A and TRAPPC6B\",\n      \"pmids\": [\"37713627\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of equal partitioning unclear\", \"Quantitative stoichiometry within each complex not measured\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated cross-species conservation of TRAPPC6A core function via humanized yeast complementation.\",\n      \"evidence\": \"CRISPR/Cas9 humanized yeast model replacing Trs33p with human TRAPPC6A\",\n      \"pmids\": [\"39273027\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single complementation readout\", \"No mechanistic dissection of TRAPPC6A-specific functions\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the canonical TRAPP tethering role of TRAPPC6A mechanistically relates to its isoform-specific roles in neurodegeneration, viral trafficking, and melanosome biogenesis remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model connecting full-length and TRAPPC6A\\u0394 functions\", \"Direct Rab GEF mechanism for mammalian TRAPPC6A not established\", \"Structure of intact human TRAPP II/III with TRAPPC6A lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 3, 9]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\"TRAPP II\", \"TRAPP III\", \"TRAPP IV\"],\n    \"partners\": [\"TRAPPC3\", \"TRAPPC2L\", \"WWOX\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}