{"gene":"TRAPPC10","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2006,"finding":"The TRAPPII-specific subunits Trs120 and Trs130 (yeast ortholog of TRAPPC10) are required for switching the GEF specificity of TRAPP from Ypt1 to Ypt31/32. A trs130ts mutation confers opposite effects on the intracellular localization of these GTPases, suggesting the Trs120-Trs130 subcomplex joins TRAPP at the late Golgi to switch GEF activity.","method":"Genetic analysis (trs130 temperature-sensitive mutants), GEF specificity assays, intracellular localization studies in yeast","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetics, GEF assays, localization), replicated across labs","pmids":["17041589"],"is_preprint":false},{"year":2005,"finding":"Trs130p (yeast ortholog of TRAPPC10), unlike Trs120p, is required for general secretion and traffic through or from the Golgi; trs130 mutations block vesicular transport at the Golgi, distinct from the early endosome-to-late Golgi recycling defect seen in trs120 mutants.","method":"Temperature-sensitive mutant analysis, electron microscopy of aberrant membrane structures, fluorescence localization with late Golgi marker Sec7p","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with specific trafficking phenotype, multiple orthogonal methods, replicated context","pmids":["16314430"],"is_preprint":false},{"year":2009,"finding":"Mammalian Trs130 (mTrs130/TRAPPC10) is a component of a mammalian TRAPPII complex that is enriched on COPI-coated vesicles and buds, acts as a GEF specifically activating Rab1, and binds to gamma1COP. Depletion of mTrs130 by shRNA leads to increased vesicles near the Golgi and cargo accumulation in an early Golgi compartment.","method":"shRNA depletion, co-immunoprecipitation (binding to gamma1COP), immunoelectron microscopy localization on COPI vesicles, GEF activity assays, cargo trafficking assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, immuno-EM, GEF assay, shRNA KD with phenotype), single lab but rigorous","pmids":["19656848"],"is_preprint":false},{"year":2011,"finding":"TRAPPC2 binds to TRAPPII-specific subunit TRAPPC9, which in turn binds to TRAPPC10, establishing TRAPPC2 as an adaptor for TRAPPII complex formation in mammalian cells. The interaction between TRAPPC2L and TRAPPC10/Trs130 is required for TRAPPII integrity.","method":"Co-immunoprecipitation in mammalian cells, disease-causing mutant analysis (D47Y TRAPPC2, deletional TRAPPC9 mutants)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reciprocal Co-IP in mammalian cells with multiple disease-relevant mutants, single lab","pmids":["21858081"],"is_preprint":false},{"year":2016,"finding":"Mammalian TRAPPII (containing TRAPPC10) acts as a GEF for both Rab18 and Rab1. Inactivation of TRAPPII-specific subunits (including via CRISPR-Cas9 deletion) reduces lipolysis, causes aberrantly large lipid droplets, and impairs Rab18 recruitment to lipid droplet surfaces. The previously documented COPI-TRAPPII interaction is required for Rab18 recruitment to lipid droplets.","method":"siRNA depletion, CRISPR-Cas9 deletion, GEF activity assays, lipid droplet imaging, Rab18 localization assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (CRISPR KO, siRNA, GEF assay, rescue experiments), two independent inactivation strategies","pmids":["28003315"],"is_preprint":false},{"year":2007,"finding":"Trs130 (yeast ortholog of TRAPPC10) localizes to the trans-Golgi and is essential for TRAPPII GEF activity toward Ypt31/32. trs130 mutant cells have low levels of Trs65 protein and are defective in GEF activity of TRAPPII and in intracellular distribution of Ypt1 and Ypt31/32.","method":"Genetic interaction analysis, physical interaction assays, GEF activity assays, fluorescence localization (trans-Golgi marker co-localization)","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic, biochemical and cellular evidence combined, multiple orthogonal methods","pmids":["17475775"],"is_preprint":false},{"year":2007,"finding":"Trs130 (TRAPPC10 ortholog) and Trs120 are conserved essential TRAPPII-specific subunits present in almost every fully sequenced eukaryotic genome. Computational analysis and experimental validation showed yeast Trs130 does not function as a transmembrane protein despite the human TMEM1 (TRAPPC10) being initially predicted to have transmembrane domains.","method":"Phylogenetic analysis, predicted secondary structure analysis, experimental demonstration that yeast Trs130 lacks transmembrane function","journal":"BMC evolutionary biology","confidence":"Low","confidence_rationale":"Tier 4 / Moderate — primarily computational with limited experimental validation of transmembrane domain absence","pmids":["17274825"],"is_preprint":false},{"year":2012,"finding":"Trs130 (TRAPPC10 ortholog) is required for both cytoplasm-to-vacuole targeting (Cvt) pathway and starvation-induced autophagy. trs130ts mutants fail to properly transport Atg8 and Atg9 to the pre-autophagosomal structure; genetic analysis placed Trs130 downstream of Atg5 and upstream of Atg1, Atg13, Atg9 and Atg14. Overexpression of Ypt31 or Ypt32, but not Ypt1, rescued autophagy defects in trs130ts mutants.","method":"Temperature-sensitive mutant analysis, GFP-Atg8 and Atg9 localization, genetic epistasis analysis, genetic suppression by Ypt31/32 overexpression","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis, localization, and genetic suppression experiments combined in multiple orthogonal approaches","pmids":["23078654"],"is_preprint":false},{"year":2012,"finding":"Genetic epistasis in yeast shows that Ypt31/32, but not Ypt1, overexpression suppresses growth and GFP-Snc1 transport phenotypes of trs130ts mutant cells, placing TRAPPII (containing Trs130/TRAPPC10 ortholog) specifically upstream of Ypt31/32 but not Ypt1 in Golgi exit trafficking.","method":"Temperature-sensitive mutant analysis, GFP-Snc1 transport assay, genetic suppression by Ypt overexpression","journal":"Genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic epistasis with multiple Rab GTPase overexpression controls","pmids":["22426882"],"is_preprint":false},{"year":2018,"finding":"The interaction between TRAPPC2L and TRAPPC10/Trs130 (TRAPPII component) is ablated by a human disease-causing missense mutation in TRAPPC2L (p.Asp37Tyr). This interaction is required for proper TRAPP II complex function; loss of TRAPPC2L-TRAPPC10 interaction results in specific membrane trafficking delays and increased levels of active RAB11.","method":"Yeast two-hybrid analysis, patient fibroblast studies, membrane trafficking assays, RAB11 activation state measurements","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus patient fibroblast functional studies, single lab, multiple methods","pmids":["30120216"],"is_preprint":false},{"year":2022,"finding":"Biallelic loss-of-function variants in TRAPPC10 cause absence of TRAPPC10 protein alongside concomitant absence of TRAPPC9, another TRAPP II component. TRAPPC10 knockout cells display a membrane trafficking defect; both TRAPPC9 reduction and the trafficking defect are rescued by wild-type but not mutant TRAPPC10 constructs. Mutant TRAPPC10 shows weakened interaction with TRAPPC2L.","method":"Patient lymphoblastoid cell studies, TRAPPC10 knockout cell lines, membrane trafficking assays, protein interaction assays, rescue experiments with wild-type vs. mutant constructs, Trappc10-/- mouse neuroanatomical analysis","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO cells, patient cells, rescue experiments, mouse model), rigorous controls including mutant construct rescue failure","pmids":["35298461"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM structures of TRAPPII (containing Trs130/TRAPPC10 ortholog) at 22-subunit resolution including a TRAPPII-Rab11 nucleotide exchange intermediate reveal that the Trs130 subunit provides a 'leg' that positions the active site distal to the membrane surface, required for steric gating against Rab1. The Trs120 subunit acts as a 'lid' to enclose the active site, enabling Rab11 to access the active site chamber.","method":"Cryo-electron microscopy structure determination, nucleotide exchange intermediate capture, structural mutagenesis analysis","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with functional validation of Trs130 'leg' role in steric gating, high-resolution mechanistic insight","pmids":["35559680"],"is_preprint":false},{"year":2021,"finding":"TRAPPII complex (containing TRAPPC10) specifically activates Rab1 and Rab11 as a GEF; the complex-specific subunits TRAPPC9 and TRAPPC10 alter protein dynamics at the Rab binding site compared to TRAPPIII. Both TRAPPII and TRAPPIII have enhanced GEF activity on lipid membranes, with conformational changes accompanying membrane association identified by HDX-MS.","method":"GEF activity biochemical assays against panel of 20 Rabs, hydrogen-deuterium exchange mass spectrometry (HDX-MS), electron microscopy","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro GEF assays with broad Rab panel plus HDX-MS conformational analysis, single lab with multiple orthogonal methods","pmids":["34229011"],"is_preprint":false},{"year":2024,"finding":"Patient-derived fibroblasts with TRAPPC6B variants show reduced levels of TRAPPC9 and TRAPPC10 alongside reduced trafficking into the Golgi apparatus and Golgi fragmentation. TRAPPC6B co-precipitates significantly more with TRAPP II than TRAPP III, suggesting TRAPPC10 levels are preferentially affected by TRAPP II disruption.","method":"Patient fibroblast protein level analysis, co-immunoprecipitation, trafficking assays, rescue with wild-type TRAPPC6B","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and patient fibroblast studies showing TRAPPC10 as part of TRAPP II, indirect finding about TRAPPC10 through TRAPPC6B studies","pmids":["37713627"],"is_preprint":false},{"year":2002,"finding":"Genetic screen in yeast identified TRS130 (TRAPPC10 ortholog) as a synthetic lethal interactor with arf1Δ. YPT31 and YPT32 were identified as high-copy suppressors of arf1Δ trs130-101, and overexpression of YPT31/32 also suppressed lethality from deletion of TRS130, placing Ypt31/32 downstream of Trs130 in the ARF-TRAPP signaling pathway.","method":"Synthetic lethal screen, high-copy suppressor screen, genetic epistasis analysis","journal":"Yeast (Chichester, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with suppressor screen, single lab, genetic-only evidence","pmids":["12210902"],"is_preprint":false},{"year":2019,"finding":"In Aspergillus nidulans, a stable Trs120/Trs130/Trs65/Tca17 TRAPPII-specific subcomplex was discovered, whose assembly onto core TRAPP generates TRAPPII through Trs20- and Trs33-dependent interactions. This modular assembly mechanism was established by exploiting constitutively active RAB mutants to rescue viability of null mutants lacking essential TRAPP subunits.","method":"Size-fractionation chromatography, single-step purification coupled to mass spectrometry, negative-stain electron microscopy, constitutively-active RAB mutant genetic rescue","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical purification with MS, EM structural analysis, and genetic validation combined, multiple orthogonal methods","pmids":["31869332"],"is_preprint":false}],"current_model":"TRAPPC10 (mammalian ortholog of yeast Trs130) is a TRAPP II complex-specific subunit that, together with TRAPPC9 and other subunits, confers GEF specificity toward Rab11 (and Rab1/Rab18) by providing a structural 'leg' that positions the catalytic active site away from the membrane for steric gating; it is required for COPI vesicle tethering at the early Golgi, Rab18-mediated lipid droplet homeostasis, and autophagy via Ypt31/32, and its loss destabilizes TRAPPC9 and causes membrane trafficking defects underlying microcephalic neurodevelopmental disease."},"narrative":{"mechanistic_narrative":"TRAPPC10 (mammalian ortholog of yeast Trs130) is a complex-specific subunit of the multisubunit TRAPPII tethering complex that controls Rab-GTPase activation during Golgi membrane traffic [PMID:17041589, PMID:19656848]. Together with TRAPPC9, it converts the guanine-nucleotide exchange (GEF) specificity of TRAPP from Rab1/Ypt1 toward Rab11/Ypt31/32, defining the TRAPPII branch of the pathway [PMID:17041589, PMID:34229011]. Cryo-EM of the 22-subunit TRAPPII–Rab11 exchange intermediate shows that the Trs130/TRAPPC10 subunit forms a structural 'leg' that positions the catalytic active site distal to the membrane, providing the steric gating that excludes Rab1 while admitting Rab11 [PMID:35559680]. The mammalian complex is enriched on COPI-coated vesicles and buds and binds gamma1COP; loss of TRAPPC10 produces accumulation of vesicles near the Golgi and cargo retention in an early Golgi compartment [PMID:19656848]. Beyond classical Golgi secretion, TRAPPII activity supports Rab18-dependent lipid-droplet homeostasis—its loss reduces lipolysis, enlarges lipid droplets, and impairs Rab18 recruitment to droplet surfaces—and is required for autophagy and cytoplasm-to-vacuole targeting acting upstream of Ypt31/32 [PMID:28003315, PMID:23078654]. Complex integrity depends on a TRAPPC2L–TRAPPC9–TRAPPC10 interaction module: disease mutations that weaken TRAPPC2L binding disrupt TRAPPII function and elevate active Rab11 [PMID:21858081, PMID:30120216]. Biallelic loss-of-function variants in TRAPPC10 abolish the protein, destabilize TRAPPC9, cause membrane-trafficking defects rescued only by wild-type TRAPPC10, and underlie a microcephalic neurodevelopmental disease [PMID:35298461].","teleology":[{"year":2002,"claim":"Established the genetic position of Trs130 in the ARF–TRAPP axis, placing the Ypt31/32 Rab GTPases downstream of it and linking TRAPPII to Arf1 function.","evidence":"Synthetic-lethal and high-copy suppressor screens with arf1Δ and TRS130 in yeast","pmids":["12210902"],"confidence":"Medium","gaps":["Genetic-only; does not show direct biochemical GEF activity","No mammalian validation at this stage"]},{"year":2005,"claim":"Distinguished Trs130's trafficking role from Trs120, showing it is required for general secretion and traffic through or from the Golgi rather than endosome-to-Golgi recycling.","evidence":"Temperature-sensitive mutants, EM of aberrant membranes, Sec7p late-Golgi localization in yeast","pmids":["16314430"],"confidence":"High","gaps":["Did not define the molecular substrate of the trafficking step","GEF target unresolved here"]},{"year":2006,"claim":"Defined the core mechanistic function: the Trs120–Trs130 subcomplex switches TRAPP GEF specificity from Ypt1 to Ypt31/32, explaining how a single tethering machine serves distinct Golgi stages.","evidence":"trs130ts genetics, GEF specificity assays, GTPase localization in yeast","pmids":["17041589"],"confidence":"High","gaps":["Structural basis of the specificity switch not established","Mammalian Rab targets not yet defined"]},{"year":2007,"claim":"Localized Trs130 to the trans-Golgi and showed it is essential for TRAPPII GEF activity and stabilizes the partner subunit Trs65, linking subunit identity to complex integrity.","evidence":"Genetic interaction, physical interaction, GEF assays, trans-Golgi colocalization in yeast","pmids":["17475775"],"confidence":"High","gaps":["Mechanism of Trs65 stabilization unresolved","No mammalian context"]},{"year":2007,"claim":"Clarified that the human TRAPPC10 (TMEM1) protein, despite predicted transmembrane domains, does not function as a transmembrane protein, refining its molecular nature as a soluble subunit.","evidence":"Phylogenetic and secondary-structure analysis with experimental test in yeast","pmids":["17274825"],"confidence":"Low","gaps":["Primarily computational with limited experimental validation","Membrane-association mode not directly characterized"]},{"year":2009,"claim":"Translated the function to mammals, identifying mTRAPPC10 as a COPI-vesicle-enriched TRAPPII component that binds gamma1COP and acts as a GEF, with depletion causing early-Golgi cargo accumulation.","evidence":"shRNA depletion, Co-IP, immuno-EM, GEF assays, cargo trafficking in mammalian cells","pmids":["19656848"],"confidence":"High","gaps":["Rab specificity reported as Rab1 here, later expanded","Single lab"]},{"year":2011,"claim":"Defined the assembly logic in mammalian cells: TRAPPC2 acts as an adaptor through TRAPPC9 to TRAPPC10, and the TRAPPC2L–TRAPPC10 interaction is required for TRAPPII integrity.","evidence":"Reciprocal Co-IP and disease-mutant analysis in mammalian cells","pmids":["21858081"],"confidence":"Medium","gaps":["Single lab","Stoichiometry and architecture not resolved structurally"]},{"year":2012,"claim":"Extended TRAPPII function beyond secretion to autophagy and the Cvt pathway, placing Trs130 upstream of Atg1/Atg13/Atg9/Atg14 with Ypt31/32 as the relevant downstream Rabs.","evidence":"trs130ts mutants, Atg8/Atg9 localization, genetic epistasis and Ypt31/32 suppression in yeast","pmids":["23078654"],"confidence":"High","gaps":["Direct biochemical coupling to autophagy machinery not shown","Mammalian autophagy role not demonstrated"]},{"year":2012,"claim":"Pinned the Rab specificity genetically, showing Ypt31/32 but not Ypt1 overexpression rescues trs130ts phenotypes in Golgi-exit cargo transport.","evidence":"GFP-Snc1 transport assays and Ypt overexpression suppression in yeast","pmids":["22426882"],"confidence":"High","gaps":["Genetic suppression does not prove direct GEF action on each Rab","Membrane context not addressed"]},{"year":2016,"claim":"Revealed a non-Golgi role, establishing mammalian TRAPPII as a Rab18 (and Rab1) GEF required for Rab18 recruitment to lipid droplets and normal lipolysis, mechanistically linked to the COPI–TRAPPII interaction.","evidence":"siRNA, CRISPR-Cas9 deletion, GEF assays, lipid-droplet imaging, Rab18 localization, rescue in mammalian cells","pmids":["28003315"],"confidence":"High","gaps":["Whether TRAPPC10 acts directly or via complex on Rab18 at droplets not separated","Connection between Golgi and droplet pools unclear"]},{"year":2018,"claim":"Linked the TRAPPC2L–TRAPPC10 interaction directly to human disease, showing a TRAPPC2L p.Asp37Tyr mutation ablates the interaction, delays trafficking, and elevates active RAB11.","evidence":"Yeast two-hybrid, patient fibroblasts, trafficking assays, RAB11 activation measurement","pmids":["30120216"],"confidence":"Medium","gaps":["Single lab","Mechanism linking RAB11 hyperactivation to phenotype not established"]},{"year":2021,"claim":"Defined the in vitro Rab repertoire, showing TRAPPII specifically activates Rab1 and Rab11 and that TRAPPC9/TRAPPC10 alter Rab-site dynamics, with membrane association enhancing GEF activity.","evidence":"GEF assays against 20-Rab panel, HDX-MS, EM","pmids":["34229011"],"confidence":"High","gaps":["Single lab","Conformational changes mapped but causal residues not fully validated"]},{"year":2022,"claim":"Provided the structural mechanism: cryo-EM of a TRAPPII–Rab11 intermediate shows TRAPPC10/Trs130 forms a 'leg' positioning the active site away from the membrane, enabling steric gating against Rab1 while Trs120 acts as a lid for Rab11 access.","evidence":"Cryo-EM structure of 22-subunit TRAPPII exchange intermediate with structural mutagenesis","pmids":["35559680"],"confidence":"High","gaps":["Dynamics of gating in a membrane bilayer not directly visualized","How the same architecture handles Rab18 not addressed"]},{"year":2022,"claim":"Established TRAPPC10 as a human disease gene, showing biallelic loss-of-function abolishes TRAPPC10 and destabilizes TRAPPC9, causes a trafficking defect rescued only by wild-type protein, and produces neuroanatomical defects in mice.","evidence":"Patient lymphoblastoid cells, TRAPPC10 KO lines, rescue experiments, Trappc10-/- mouse neuroanatomy","pmids":["35298461"],"confidence":"High","gaps":["Cell-type basis of neurodevelopmental phenotype not defined","Link from trafficking defect to brain phenotype mechanistically incomplete"]},{"year":2024,"claim":"Reinforced TRAPPC10 as a TRAPPII-preferential subunit, showing TRAPPC6B variants reduce TRAPPC9/TRAPPC10 levels and impair Golgi trafficking, with TRAPPC6B associating more with TRAPPII.","evidence":"Patient fibroblast protein-level analysis, Co-IP, trafficking assays, rescue in mammalian cells","pmids":["37713627"],"confidence":"Medium","gaps":["Indirect finding via TRAPPC6B","Single lab"]},{"year":null,"claim":"How TRAPPC10 mechanistically couples its membrane-distal GEF architecture to the distinct downstream consequences (Golgi secretion vs lipid-droplet Rab18 activation vs autophagy) and how its loss produces the specific microcephalic neurodevelopmental phenotype remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of TRAPPII engaging Rab18 at lipid droplets","Cell-type-specific requirement in brain not defined","Direct vs complex-mediated contribution of TRAPPC10 to each Rab not separated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,12]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,2,5]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[2]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[4]}],"complexes":["TRAPPII"],"partners":["TRAPPC9","TRAPPC2L","TRAPPC2","GAMMA1COP","TRAPPC6B","RAB11","RAB18","RAB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P48553","full_name":"Trafficking protein particle complex subunit 10","aliases":["Epilepsy holoprosencephaly candidate 1 protein","EHOC-1","Protein GT334","Trafficking protein particle complex subunit TMEM1","Transport protein particle subunit TMEM1","TRAPP subunit TMEM1"],"length_aa":1259,"mass_kda":142.2,"function":"Specific subunit of the TRAPP (transport protein particle) II complex, a highly conserved vesicle tethering complex that functions in late Golgi trafficking as a membrane tether","subcellular_location":"Golgi apparatus, cis-Golgi network","url":"https://www.uniprot.org/uniprotkb/P48553/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRAPPC10","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TRAPPC2","stoichiometry":10.0},{"gene":"TRAPPC1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TRAPPC10","total_profiled":1310},"omim":[{"mim_id":"620027","title":"NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, SHORT STATURE, AND SPEECH DELAY; NEDMISS","url":"https://www.omim.org/entry/620027"},{"mim_id":"618331","title":"ENCEPHALOPATHY, PROGRESSIVE, EARLY-ONSET, WITH EPISODIC RHABDOMYOLYSIS; PEERB","url":"https://www.omim.org/entry/618331"},{"mim_id":"610970","title":"TRAFFICKING PROTEIN PARTICLE COMPLEX, SUBUNIT 2L; TRAPPC2L","url":"https://www.omim.org/entry/610970"},{"mim_id":"602103","title":"TRAFFICKING PROTEIN PARTICLE COMPLEX, SUBUNIT 10; TRAPPC10","url":"https://www.omim.org/entry/602103"}],"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/TRAPPC10"},"hgnc":{"alias_symbol":["EHOC-1","TRS130"],"prev_symbol":["TMEM1"]},"alphafold":{"accession":"P48553","domains":[{"cath_id":"3.40.50","chopping":"21-212","consensus_level":"high","plddt":83.0633,"start":21,"end":212},{"cath_id":"-","chopping":"220-474","consensus_level":"medium","plddt":90.6413,"start":220,"end":474},{"cath_id":"2.60.40.10","chopping":"579-661_720-782","consensus_level":"high","plddt":78.411,"start":579,"end":782},{"cath_id":"2.60.40.10","chopping":"955-1054","consensus_level":"high","plddt":81.2664,"start":955,"end":1054},{"cath_id":"2.60.40.10","chopping":"1060-1170_1225-1247","consensus_level":"medium","plddt":82.3307,"start":1060,"end":1247},{"cath_id":"2.60.40","chopping":"797-885","consensus_level":"high","plddt":80.9497,"start":797,"end":885}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P48553","model_url":"https://alphafold.ebi.ac.uk/files/AF-P48553-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P48553-F1-predicted_aligned_error_v6.png","plddt_mean":79.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRAPPC10","jax_strain_url":"https://www.jax.org/strain/search?query=TRAPPC10"},"sequence":{"accession":"P48553","fasta_url":"https://rest.uniprot.org/uniprotkb/P48553.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P48553/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P48553"}},"corpus_meta":[{"pmid":"17041589","id":"PMC_17041589","title":"TRAPPII subunits are required for the specificity switch of a Ypt-Rab GEF.","date":"2006","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/17041589","citation_count":132,"is_preprint":false},{"pmid":"16314430","id":"PMC_16314430","title":"Mutants in trs120 disrupt traffic from the early endosome to the late Golgi.","date":"2005","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16314430","citation_count":106,"is_preprint":false},{"pmid":"19656848","id":"PMC_19656848","title":"mTrs130 is a component of a mammalian TRAPPII complex, a Rab1 GEF that binds to COPI-coated vesicles.","date":"2009","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/19656848","citation_count":106,"is_preprint":false},{"pmid":"19942856","id":"PMC_19942856","title":"A genome-wide RNA interference screen identifies two novel components of the metazoan secretory pathway.","date":"2009","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/19942856","citation_count":90,"is_preprint":false},{"pmid":"28003315","id":"PMC_28003315","title":"COPI-TRAPPII activates Rab18 and regulates its lipid droplet association.","date":"2016","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/28003315","citation_count":81,"is_preprint":false},{"pmid":"26474971","id":"PMC_26474971","title":"A genome-wide approach to link genotype to clinical outcome by utilizing next generation sequencing and gene chip data of 6,697 breast cancer patients.","date":"2015","source":"Genome medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26474971","citation_count":70,"is_preprint":false},{"pmid":"25831508","id":"PMC_25831508","title":"TRAPPII regulates exocytic Golgi exit by mediating nucleotide exchange on the Ypt31 ortholog RabERAB11.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25831508","citation_count":56,"is_preprint":false},{"pmid":"21858081","id":"PMC_21858081","title":"The adaptor function of TRAPPC2 in mammalian TRAPPs explains TRAPPC2-associated SEDT and TRAPPC9-associated congenital intellectual disability.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21858081","citation_count":54,"is_preprint":false},{"pmid":"7633421","id":"PMC_7633421","title":"Isolation and characterization of a candidate gene for progressive myoclonus epilepsy on 21q22.3.","date":"1995","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7633421","citation_count":53,"is_preprint":false},{"pmid":"30167849","id":"PMC_30167849","title":"Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability.","date":"2018","source":"Human 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ortholog of TRAPPC10) are required for switching the GEF specificity of TRAPP from Ypt1 to Ypt31/32. A trs130ts mutation confers opposite effects on the intracellular localization of these GTPases, suggesting the Trs120-Trs130 subcomplex joins TRAPP at the late Golgi to switch GEF activity.\",\n      \"method\": \"Genetic analysis (trs130 temperature-sensitive mutants), GEF specificity assays, intracellular localization studies in yeast\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetics, GEF assays, localization), replicated across labs\",\n      \"pmids\": [\"17041589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Trs130p (yeast ortholog of TRAPPC10), unlike Trs120p, is required for general secretion and traffic through or from the Golgi; trs130 mutations block vesicular transport at the Golgi, distinct from the early endosome-to-late Golgi recycling defect seen in trs120 mutants.\",\n      \"method\": \"Temperature-sensitive mutant analysis, electron microscopy of aberrant membrane structures, fluorescence localization with late Golgi marker Sec7p\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with specific trafficking phenotype, multiple orthogonal methods, replicated context\",\n      \"pmids\": [\"16314430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Mammalian Trs130 (mTrs130/TRAPPC10) is a component of a mammalian TRAPPII complex that is enriched on COPI-coated vesicles and buds, acts as a GEF specifically activating Rab1, and binds to gamma1COP. Depletion of mTrs130 by shRNA leads to increased vesicles near the Golgi and cargo accumulation in an early Golgi compartment.\",\n      \"method\": \"shRNA depletion, co-immunoprecipitation (binding to gamma1COP), immunoelectron microscopy localization on COPI vesicles, GEF activity assays, cargo trafficking assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, immuno-EM, GEF assay, shRNA KD with phenotype), single lab but rigorous\",\n      \"pmids\": [\"19656848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TRAPPC2 binds to TRAPPII-specific subunit TRAPPC9, which in turn binds to TRAPPC10, establishing TRAPPC2 as an adaptor for TRAPPII complex formation in mammalian cells. The interaction between TRAPPC2L and TRAPPC10/Trs130 is required for TRAPPII integrity.\",\n      \"method\": \"Co-immunoprecipitation in mammalian cells, disease-causing mutant analysis (D47Y TRAPPC2, deletional TRAPPC9 mutants)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reciprocal Co-IP in mammalian cells with multiple disease-relevant mutants, single lab\",\n      \"pmids\": [\"21858081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mammalian TRAPPII (containing TRAPPC10) acts as a GEF for both Rab18 and Rab1. Inactivation of TRAPPII-specific subunits (including via CRISPR-Cas9 deletion) reduces lipolysis, causes aberrantly large lipid droplets, and impairs Rab18 recruitment to lipid droplet surfaces. The previously documented COPI-TRAPPII interaction is required for Rab18 recruitment to lipid droplets.\",\n      \"method\": \"siRNA depletion, CRISPR-Cas9 deletion, GEF activity assays, lipid droplet imaging, Rab18 localization assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (CRISPR KO, siRNA, GEF assay, rescue experiments), two independent inactivation strategies\",\n      \"pmids\": [\"28003315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Trs130 (yeast ortholog of TRAPPC10) localizes to the trans-Golgi and is essential for TRAPPII GEF activity toward Ypt31/32. trs130 mutant cells have low levels of Trs65 protein and are defective in GEF activity of TRAPPII and in intracellular distribution of Ypt1 and Ypt31/32.\",\n      \"method\": \"Genetic interaction analysis, physical interaction assays, GEF activity assays, fluorescence localization (trans-Golgi marker co-localization)\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic, biochemical and cellular evidence combined, multiple orthogonal methods\",\n      \"pmids\": [\"17475775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Trs130 (TRAPPC10 ortholog) and Trs120 are conserved essential TRAPPII-specific subunits present in almost every fully sequenced eukaryotic genome. Computational analysis and experimental validation showed yeast Trs130 does not function as a transmembrane protein despite the human TMEM1 (TRAPPC10) being initially predicted to have transmembrane domains.\",\n      \"method\": \"Phylogenetic analysis, predicted secondary structure analysis, experimental demonstration that yeast Trs130 lacks transmembrane function\",\n      \"journal\": \"BMC evolutionary biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Moderate — primarily computational with limited experimental validation of transmembrane domain absence\",\n      \"pmids\": [\"17274825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Trs130 (TRAPPC10 ortholog) is required for both cytoplasm-to-vacuole targeting (Cvt) pathway and starvation-induced autophagy. trs130ts mutants fail to properly transport Atg8 and Atg9 to the pre-autophagosomal structure; genetic analysis placed Trs130 downstream of Atg5 and upstream of Atg1, Atg13, Atg9 and Atg14. Overexpression of Ypt31 or Ypt32, but not Ypt1, rescued autophagy defects in trs130ts mutants.\",\n      \"method\": \"Temperature-sensitive mutant analysis, GFP-Atg8 and Atg9 localization, genetic epistasis analysis, genetic suppression by Ypt31/32 overexpression\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis, localization, and genetic suppression experiments combined in multiple orthogonal approaches\",\n      \"pmids\": [\"23078654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Genetic epistasis in yeast shows that Ypt31/32, but not Ypt1, overexpression suppresses growth and GFP-Snc1 transport phenotypes of trs130ts mutant cells, placing TRAPPII (containing Trs130/TRAPPC10 ortholog) specifically upstream of Ypt31/32 but not Ypt1 in Golgi exit trafficking.\",\n      \"method\": \"Temperature-sensitive mutant analysis, GFP-Snc1 transport assay, genetic suppression by Ypt overexpression\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic epistasis with multiple Rab GTPase overexpression controls\",\n      \"pmids\": [\"22426882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The interaction between TRAPPC2L and TRAPPC10/Trs130 (TRAPPII component) is ablated by a human disease-causing missense mutation in TRAPPC2L (p.Asp37Tyr). This interaction is required for proper TRAPP II complex function; loss of TRAPPC2L-TRAPPC10 interaction results in specific membrane trafficking delays and increased levels of active RAB11.\",\n      \"method\": \"Yeast two-hybrid analysis, patient fibroblast studies, membrane trafficking assays, RAB11 activation state measurements\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus patient fibroblast functional studies, single lab, multiple methods\",\n      \"pmids\": [\"30120216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Biallelic loss-of-function variants in TRAPPC10 cause absence of TRAPPC10 protein alongside concomitant absence of TRAPPC9, another TRAPP II component. TRAPPC10 knockout cells display a membrane trafficking defect; both TRAPPC9 reduction and the trafficking defect are rescued by wild-type but not mutant TRAPPC10 constructs. Mutant TRAPPC10 shows weakened interaction with TRAPPC2L.\",\n      \"method\": \"Patient lymphoblastoid cell studies, TRAPPC10 knockout cell lines, membrane trafficking assays, protein interaction assays, rescue experiments with wild-type vs. mutant constructs, Trappc10-/- mouse neuroanatomical analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO cells, patient cells, rescue experiments, mouse model), rigorous controls including mutant construct rescue failure\",\n      \"pmids\": [\"35298461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structures of TRAPPII (containing Trs130/TRAPPC10 ortholog) at 22-subunit resolution including a TRAPPII-Rab11 nucleotide exchange intermediate reveal that the Trs130 subunit provides a 'leg' that positions the active site distal to the membrane surface, required for steric gating against Rab1. The Trs120 subunit acts as a 'lid' to enclose the active site, enabling Rab11 to access the active site chamber.\",\n      \"method\": \"Cryo-electron microscopy structure determination, nucleotide exchange intermediate capture, structural mutagenesis analysis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with functional validation of Trs130 'leg' role in steric gating, high-resolution mechanistic insight\",\n      \"pmids\": [\"35559680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRAPPII complex (containing TRAPPC10) specifically activates Rab1 and Rab11 as a GEF; the complex-specific subunits TRAPPC9 and TRAPPC10 alter protein dynamics at the Rab binding site compared to TRAPPIII. Both TRAPPII and TRAPPIII have enhanced GEF activity on lipid membranes, with conformational changes accompanying membrane association identified by HDX-MS.\",\n      \"method\": \"GEF activity biochemical assays against panel of 20 Rabs, hydrogen-deuterium exchange mass spectrometry (HDX-MS), electron microscopy\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro GEF assays with broad Rab panel plus HDX-MS conformational analysis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34229011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Patient-derived fibroblasts with TRAPPC6B variants show reduced levels of TRAPPC9 and TRAPPC10 alongside reduced trafficking into the Golgi apparatus and Golgi fragmentation. TRAPPC6B co-precipitates significantly more with TRAPP II than TRAPP III, suggesting TRAPPC10 levels are preferentially affected by TRAPP II disruption.\",\n      \"method\": \"Patient fibroblast protein level analysis, co-immunoprecipitation, trafficking assays, rescue with wild-type TRAPPC6B\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and patient fibroblast studies showing TRAPPC10 as part of TRAPP II, indirect finding about TRAPPC10 through TRAPPC6B studies\",\n      \"pmids\": [\"37713627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Genetic screen in yeast identified TRS130 (TRAPPC10 ortholog) as a synthetic lethal interactor with arf1Δ. YPT31 and YPT32 were identified as high-copy suppressors of arf1Δ trs130-101, and overexpression of YPT31/32 also suppressed lethality from deletion of TRS130, placing Ypt31/32 downstream of Trs130 in the ARF-TRAPP signaling pathway.\",\n      \"method\": \"Synthetic lethal screen, high-copy suppressor screen, genetic epistasis analysis\",\n      \"journal\": \"Yeast (Chichester, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with suppressor screen, single lab, genetic-only evidence\",\n      \"pmids\": [\"12210902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In Aspergillus nidulans, a stable Trs120/Trs130/Trs65/Tca17 TRAPPII-specific subcomplex was discovered, whose assembly onto core TRAPP generates TRAPPII through Trs20- and Trs33-dependent interactions. This modular assembly mechanism was established by exploiting constitutively active RAB mutants to rescue viability of null mutants lacking essential TRAPP subunits.\",\n      \"method\": \"Size-fractionation chromatography, single-step purification coupled to mass spectrometry, negative-stain electron microscopy, constitutively-active RAB mutant genetic rescue\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical purification with MS, EM structural analysis, and genetic validation combined, multiple orthogonal methods\",\n      \"pmids\": [\"31869332\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRAPPC10 (mammalian ortholog of yeast Trs130) is a TRAPP II complex-specific subunit that, together with TRAPPC9 and other subunits, confers GEF specificity toward Rab11 (and Rab1/Rab18) by providing a structural 'leg' that positions the catalytic active site away from the membrane for steric gating; it is required for COPI vesicle tethering at the early Golgi, Rab18-mediated lipid droplet homeostasis, and autophagy via Ypt31/32, and its loss destabilizes TRAPPC9 and causes membrane trafficking defects underlying microcephalic neurodevelopmental disease.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRAPPC10 (mammalian ortholog of yeast Trs130) is a complex-specific subunit of the multisubunit TRAPPII tethering complex that controls Rab-GTPase activation during Golgi membrane traffic [#0, #2]. Together with TRAPPC9, it converts the guanine-nucleotide exchange (GEF) specificity of TRAPP from Rab1/Ypt1 toward Rab11/Ypt31/32, defining the TRAPPII branch of the pathway [#0, #12]. Cryo-EM of the 22-subunit TRAPPII–Rab11 exchange intermediate shows that the Trs130/TRAPPC10 subunit forms a structural 'leg' that positions the catalytic active site distal to the membrane, providing the steric gating that excludes Rab1 while admitting Rab11 [#11]. The mammalian complex is enriched on COPI-coated vesicles and buds and binds gamma1COP; loss of TRAPPC10 produces accumulation of vesicles near the Golgi and cargo retention in an early Golgi compartment [#2]. Beyond classical Golgi secretion, TRAPPII activity supports Rab18-dependent lipid-droplet homeostasis—its loss reduces lipolysis, enlarges lipid droplets, and impairs Rab18 recruitment to droplet surfaces—and is required for autophagy and cytoplasm-to-vacuole targeting acting upstream of Ypt31/32 [#4, #7]. Complex integrity depends on a TRAPPC2L–TRAPPC9–TRAPPC10 interaction module: disease mutations that weaken TRAPPC2L binding disrupt TRAPPII function and elevate active Rab11 [#3, #9]. Biallelic loss-of-function variants in TRAPPC10 abolish the protein, destabilize TRAPPC9, cause membrane-trafficking defects rescued only by wild-type TRAPPC10, and underlie a microcephalic neurodevelopmental disease [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established the genetic position of Trs130 in the ARF–TRAPP axis, placing the Ypt31/32 Rab GTPases downstream of it and linking TRAPPII to Arf1 function.\",\n      \"evidence\": \"Synthetic-lethal and high-copy suppressor screens with arf1\\u0394 and TRS130 in yeast\",\n      \"pmids\": [\"12210902\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Genetic-only; does not show direct biochemical GEF activity\", \"No mammalian validation at this stage\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Distinguished Trs130's trafficking role from Trs120, showing it is required for general secretion and traffic through or from the Golgi rather than endosome-to-Golgi recycling.\",\n      \"evidence\": \"Temperature-sensitive mutants, EM of aberrant membranes, Sec7p late-Golgi localization in yeast\",\n      \"pmids\": [\"16314430\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Did not define the molecular substrate of the trafficking step\", \"GEF target unresolved here\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the core mechanistic function: the Trs120–Trs130 subcomplex switches TRAPP GEF specificity from Ypt1 to Ypt31/32, explaining how a single tethering machine serves distinct Golgi stages.\",\n      \"evidence\": \"trs130ts genetics, GEF specificity assays, GTPase localization in yeast\",\n      \"pmids\": [\"17041589\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structural basis of the specificity switch not established\", \"Mammalian Rab targets not yet defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Localized Trs130 to the trans-Golgi and showed it is essential for TRAPPII GEF activity and stabilizes the partner subunit Trs65, linking subunit identity to complex integrity.\",\n      \"evidence\": \"Genetic interaction, physical interaction, GEF assays, trans-Golgi colocalization in yeast\",\n      \"pmids\": [\"17475775\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism of Trs65 stabilization unresolved\", \"No mammalian context\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Clarified that the human TRAPPC10 (TMEM1) protein, despite predicted transmembrane domains, does not function as a transmembrane protein, refining its molecular nature as a soluble subunit.\",\n      \"evidence\": \"Phylogenetic and secondary-structure analysis with experimental test in yeast\",\n      \"pmids\": [\"17274825\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Primarily computational with limited experimental validation\", \"Membrane-association mode not directly characterized\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Translated the function to mammals, identifying mTRAPPC10 as a COPI-vesicle-enriched TRAPPII component that binds gamma1COP and acts as a GEF, with depletion causing early-Golgi cargo accumulation.\",\n      \"evidence\": \"shRNA depletion, Co-IP, immuno-EM, GEF assays, cargo trafficking in mammalian cells\",\n      \"pmids\": [\"19656848\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Rab specificity reported as Rab1 here, later expanded\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the assembly logic in mammalian cells: TRAPPC2 acts as an adaptor through TRAPPC9 to TRAPPC10, and the TRAPPC2L–TRAPPC10 interaction is required for TRAPPII integrity.\",\n      \"evidence\": \"Reciprocal Co-IP and disease-mutant analysis in mammalian cells\",\n      \"pmids\": [\"21858081\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single lab\", \"Stoichiometry and architecture not resolved structurally\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended TRAPPII function beyond secretion to autophagy and the Cvt pathway, placing Trs130 upstream of Atg1/Atg13/Atg9/Atg14 with Ypt31/32 as the relevant downstream Rabs.\",\n      \"evidence\": \"trs130ts mutants, Atg8/Atg9 localization, genetic epistasis and Ypt31/32 suppression in yeast\",\n      \"pmids\": [\"23078654\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct biochemical coupling to autophagy machinery not shown\", \"Mammalian autophagy role not demonstrated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Pinned the Rab specificity genetically, showing Ypt31/32 but not Ypt1 overexpression rescues trs130ts phenotypes in Golgi-exit cargo transport.\",\n      \"evidence\": \"GFP-Snc1 transport assays and Ypt overexpression suppression in yeast\",\n      \"pmids\": [\"22426882\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Genetic suppression does not prove direct GEF action on each Rab\", \"Membrane context not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed a non-Golgi role, establishing mammalian TRAPPII as a Rab18 (and Rab1) GEF required for Rab18 recruitment to lipid droplets and normal lipolysis, mechanistically linked to the COPI–TRAPPII interaction.\",\n      \"evidence\": \"siRNA, CRISPR-Cas9 deletion, GEF assays, lipid-droplet imaging, Rab18 localization, rescue in mammalian cells\",\n      \"pmids\": [\"28003315\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether TRAPPC10 acts directly or via complex on Rab18 at droplets not separated\", \"Connection between Golgi and droplet pools unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked the TRAPPC2L–TRAPPC10 interaction directly to human disease, showing a TRAPPC2L p.Asp37Tyr mutation ablates the interaction, delays trafficking, and elevates active RAB11.\",\n      \"evidence\": \"Yeast two-hybrid, patient fibroblasts, trafficking assays, RAB11 activation measurement\",\n      \"pmids\": [\"30120216\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single lab\", \"Mechanism linking RAB11 hyperactivation to phenotype not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the in vitro Rab repertoire, showing TRAPPII specifically activates Rab1 and Rab11 and that TRAPPC9/TRAPPC10 alter Rab-site dynamics, with membrane association enhancing GEF activity.\",\n      \"evidence\": \"GEF assays against 20-Rab panel, HDX-MS, EM\",\n      \"pmids\": [\"34229011\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single lab\", \"Conformational changes mapped but causal residues not fully validated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided the structural mechanism: cryo-EM of a TRAPPII–Rab11 intermediate shows TRAPPC10/Trs130 forms a 'leg' positioning the active site away from the membrane, enabling steric gating against Rab1 while Trs120 acts as a lid for Rab11 access.\",\n      \"evidence\": \"Cryo-EM structure of 22-subunit TRAPPII exchange intermediate with structural mutagenesis\",\n      \"pmids\": [\"35559680\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Dynamics of gating in a membrane bilayer not directly visualized\", \"How the same architecture handles Rab18 not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established TRAPPC10 as a human disease gene, showing biallelic loss-of-function abolishes TRAPPC10 and destabilizes TRAPPC9, causes a trafficking defect rescued only by wild-type protein, and produces neuroanatomical defects in mice.\",\n      \"evidence\": \"Patient lymphoblastoid cells, TRAPPC10 KO lines, rescue experiments, Trappc10-/- mouse neuroanatomy\",\n      \"pmids\": [\"35298461\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Cell-type basis of neurodevelopmental phenotype not defined\", \"Link from trafficking defect to brain phenotype mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Reinforced TRAPPC10 as a TRAPPII-preferential subunit, showing TRAPPC6B variants reduce TRAPPC9/TRAPPC10 levels and impair Golgi trafficking, with TRAPPC6B associating more with TRAPPII.\",\n      \"evidence\": \"Patient fibroblast protein-level analysis, Co-IP, trafficking assays, rescue in mammalian cells\",\n      \"pmids\": [\"37713627\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Indirect finding via TRAPPC6B\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TRAPPC10 mechanistically couples its membrane-distal GEF architecture to the distinct downstream consequences (Golgi secretion vs lipid-droplet Rab18 activation vs autophagy) and how its loss produces the specific microcephalic neurodevelopmental phenotype remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structural model of TRAPPII engaging Rab18 at lipid droplets\", \"Cell-type-specific requirement in brain not defined\", \"Direct vs complex-mediated contribution of TRAPPC10 to each Rab not separated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005085\", \"supporting_discovery_ids\": [0, 2, 4, 12]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 2, 5]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\n      \"TRAPPII\"\n    ],\n    \"partners\": [\n      \"TRAPPC9\",\n      \"TRAPPC2L\",\n      \"TRAPPC2\",\n      \"gamma1COP\",\n      \"TRAPPC6B\",\n      \"RAB11\",\n      \"RAB18\",\n      \"RAB1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}