{"gene":"TMCC3","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2016,"finding":"TMCC3 protein self-assembles into oligomers and localizes to the endoplasmic reticulum through its transmembrane domains. TMCC3 associates with 14-3-3 proteins as identified by immunoprecipitation and mass spectrometry.","method":"Recombinant protein expression with deletion mutants, immunostaining, confocal microscopy, immunoprecipitation, mass spectrometry","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (subcellular localization by imaging, oligomerization by deletion mutants, binding partner by Co-IP/MS) in a single lab study","pmids":["27697108"],"is_preprint":false},{"year":2019,"finding":"TMCC3 localizes specifically at three-way junctions of the peripheral ER tubular network. Its N-terminal coiled-coil domain is required for three-way junction localization. TMCC3 binds to atlastins through its C-terminal transmembrane domains, but the coiled-coil domain is required for localization independently of atlastin binding. TMCC3 knockdown reduces the number of three-way junctions and expands ER sheets, diminishing the tubular ER network; this phenotype is partially rescued by atlastin-2 overexpression, indicating TMCC3 supports atlastin activity.","method":"Transfection of TEX28 family members in U2OS cells, fluorescence microscopy, domain truncation mutants, knockdown (RNAi), overexpression rescue experiments","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (localization, domain mutagenesis, knockdown with defined phenotype, rescue epistasis) in a focused mechanistic study","pmids":["31696206"],"is_preprint":false},{"year":2021,"finding":"TMCC3 directly interacts with AKT through its N-terminal 1–153 amino acid domain, as demonstrated by cell-free biochemical assay and co-immunoprecipitation with domain mapping. TMCC3 positively regulates AKT activation: TMCC3 silencing reduces AKT activation while overexpression enhances it. The AKT-interacting domain of TMCC3 is required for TMCC3-induced AKT activation, breast cancer stem cell self-renewal, and metastasis.","method":"Cell-free biochemical binding assay, co-immunoprecipitation, domain truncation/mapping, siRNA knockdown, overexpression, in vitro mammosphere and ALDH assays, in vivo xenograft and metastasis models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, cell-free binding assay, domain mapping, functional KD and OE with multiple orthogonal readouts in a single rigorous study","pmids":["33742122"],"is_preprint":false},{"year":2022,"finding":"14-3-3γ binds to the N-terminus of TMCC3 via deduced phospho-serine binding motifs and negatively regulates TMCC3 localization to ER three-way junctions. Overexpression of 14-3-3γ reduces TMCC3 at three-way junctions and decreases junction number. A TMCC3 serine-to-alanine mutant in the 14-3-3 binding motif shows reduced 14-3-3γ binding and is more resistant to 14-3-3γ-driven displacement from three-way junctions. The phosphorylation-dependent 14-3-3γ binding thus underlies remodeling of the reticular ER network.","method":"Co-immunoprecipitation, overexpression, site-directed mutagenesis (serine-to-alanine), fluorescence microscopy, TMCC3 knockdown rescue assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, structure-function mutagenesis, knockdown/rescue with defined ER morphology phenotype, multiple orthogonal methods in single focused study","pmids":["36549645"],"is_preprint":false},{"year":2024,"finding":"PPARγ directly and positively regulates Tmcc3 gene transcription through a PPARγ-responsive element in the 5'-region of Tmcc3-1b and -1c isoforms, as shown by reporter assays and EMSA. Liver-specific PPARγ knockout ameliorates elevated TMCC3-1B expression in ob/ob fatty liver mice.","method":"Reporter assay, electrophoretic mobility shift assay (EMSA), liver-specific knockout mouse model, identification of three Tmcc3 exon-1 variants","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — EMSA and reporter assay establish direct PPARγ binding and transactivation; knockout confirms in vivo relevance; single lab","pmids":["39326649"],"is_preprint":false}],"current_model":"TMCC3 is an ER-resident transmembrane protein that self-oligomerizes and localizes specifically to ER tubule three-way junctions via its N-terminal coiled-coil domain, where it promotes the tubular ER network by supporting atlastin GTPase activity; its junction localization is negatively regulated by phosphorylation-dependent binding of 14-3-3γ; in cancer cells, TMCC3 also directly binds and activates AKT through its N-terminal domain to promote breast cancer stem cell self-renewal and metastasis; and its transcription is driven by PPARγ in fatty liver."},"narrative":{"mechanistic_narrative":"TMCC3 is an endoplasmic reticulum transmembrane protein that shapes the tubular ER network by localizing specifically to ER tubule three-way junctions [PMID:31696206]. It self-assembles into oligomers and is anchored in the ER through its transmembrane domains, while its N-terminal coiled-coil domain directs the protein to three-way junctions [PMID:27697108, PMID:31696206]. TMCC3 binds atlastin GTPases through its C-terminal transmembrane segments, and TMCC3 loss reduces three-way junctions and expands ER sheets—a phenotype partially rescued by atlastin-2 overexpression, establishing that TMCC3 supports atlastin activity in promoting the reticular ER [PMID:31696206]. Junction localization is negatively regulated by phosphorylation-dependent binding of 14-3-3γ to the TMCC3 N-terminus, which displaces TMCC3 from three-way junctions and remodels the ER network [PMID:36549645]. Beyond ER morphogenesis, TMCC3 directly binds AKT via its N-terminal 1–153 residue domain and positively regulates AKT activation, and this interaction drives breast cancer stem cell self-renewal and metastasis [PMID:33742122]. TMCC3 transcription is directly activated by PPARγ through a responsive element in its 5' region, accounting for elevated expression in fatty liver [PMID:39326649].","teleology":[{"year":2016,"claim":"Establishing where TMCC3 resides and how it is organized was the first step in defining its cellular role, showing it is an ER-anchored protein that oligomerizes and engages 14-3-3 proteins.","evidence":"Deletion-mutant expression, confocal immunostaining, and immunoprecipitation/mass spectrometry of recombinant TMCC3","pmids":["27697108"],"confidence":"Medium","gaps":["The functional consequence of oligomerization was not defined","The specific 14-3-3 isoform and the regulatory role of the interaction were not resolved"]},{"year":2019,"claim":"This work resolved the molecular function of TMCC3 in ER architecture, demonstrating that it concentrates at three-way junctions via its coiled-coil domain and supports atlastin-driven formation of the tubular ER network.","evidence":"Domain-truncation mapping, fluorescence microscopy, RNAi knockdown with defined ER-morphology phenotype, and atlastin-2 overexpression rescue in U2OS cells","pmids":["31696206"],"confidence":"High","gaps":["The biochemical mechanism by which TMCC3 enhances atlastin GTPase activity was not determined","Whether junction targeting is dynamically regulated was not addressed"]},{"year":2021,"claim":"An unexpected signaling function was uncovered, showing TMCC3 directly binds and activates AKT to drive breast cancer stem cell self-renewal and metastasis—linking the ER protein to oncogenic signaling.","evidence":"Cell-free binding assay, reciprocal Co-IP with domain mapping, siRNA/overexpression, mammosphere and ALDH assays, and xenograft/metastasis models","pmids":["33742122"],"confidence":"High","gaps":["How an ER membrane protein engages cytosolic AKT mechanistically was not resolved","Whether AKT activation is connected to TMCC3's ER junction role is unknown"]},{"year":2022,"claim":"The regulatory logic of TMCC3 junction localization was defined, showing phosphorylation-dependent 14-3-3γ binding to the N-terminus displaces TMCC3 from three-way junctions and remodels the ER network.","evidence":"Reciprocal Co-IP, serine-to-alanine site-directed mutagenesis, overexpression, and knockdown/rescue with ER-morphology readout","pmids":["36549645"],"confidence":"High","gaps":["The kinase that phosphorylates the 14-3-3 binding motif was not identified","The physiological signal triggering 14-3-3γ-mediated remodeling was not defined"]},{"year":2024,"claim":"Transcriptional control of TMCC3 was established, identifying PPARγ as a direct activator of Tmcc3 isoforms and linking its upregulation to fatty liver.","evidence":"Reporter assays, EMSA, identification of exon-1 variants, and liver-specific PPARγ knockout in ob/ob mice","pmids":["39326649"],"confidence":"Medium","gaps":["The functional role of elevated TMCC3 in hepatic lipid metabolism was not established","Whether the ER or AKT functions mediate the fatty-liver phenotype is unknown"]},{"year":null,"claim":"How TMCC3's distinct activities—ER three-way junction organization, atlastin support, and direct AKT activation—are mechanistically integrated within one protein remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model connecting the coiled-coil, AKT-binding, and transmembrane regions","Whether ER architecture and AKT signaling functions are coupled is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2]}],"complexes":[],"partners":["ATL2","AKT1","YWHAG","PPARG"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9ULS5","full_name":"Transmembrane and coiled-coil domain protein 3","aliases":[],"length_aa":477,"mass_kda":53.8,"function":"","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q9ULS5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMCC3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ENO1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TMCC3","total_profiled":1310},"omim":[{"mim_id":"617459","title":"TRANSMEMBRANE AND COILED-COIL DOMAIN FAMILY, MEMBER 3; TMCC3","url":"https://www.omim.org/entry/617459"},{"mim_id":"616242","title":"TRANSMEMBRANE AND COILED-COIL DOMAIN FAMILY, MEMBER 1; TMCC1","url":"https://www.omim.org/entry/616242"},{"mim_id":"601280","title":"MAB21-LIKE 1; MAB21L1","url":"https://www.omim.org/entry/601280"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TMCC3"},"hgnc":{"alias_symbol":["KIAA1145"],"prev_symbol":[]},"alphafold":{"accession":"Q9ULS5","domains":[{"cath_id":"1.20.5","chopping":"445-477","consensus_level":"medium","plddt":76.197,"start":445,"end":477}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULS5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULS5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULS5-F1-predicted_aligned_error_v6.png","plddt_mean":69.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMCC3","jax_strain_url":"https://www.jax.org/strain/search?query=TMCC3"},"sequence":{"accession":"Q9ULS5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9ULS5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9ULS5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULS5"}},"corpus_meta":[{"pmid":"29367434","id":"PMC_29367434","title":"Proteomics Profiling of CLL Versus Healthy B-cells Identifies Putative Therapeutic Targets and a Subtype-independent Signature of Spliceosome Dysregulation.","date":"2018","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/29367434","citation_count":51,"is_preprint":false},{"pmid":"36591938","id":"PMC_36591938","title":"NamiRNA-enhancer network of miR-492 activates the NR2C1-TGF-β/Smad3 pathway to promote epithelial-mesenchymal transition of pancreatic cancer.","date":"2023","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/36591938","citation_count":22,"is_preprint":false},{"pmid":"16473350","id":"PMC_16473350","title":"Identification of novel genes regulated in the developing human ventral mesencephalon.","date":"2006","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/16473350","citation_count":20,"is_preprint":false},{"pmid":"31568004","id":"PMC_31568004","title":"Identification of gene and microRNA changes in response to smoking in human airway epithelium by bioinformatics analyses.","date":"2019","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31568004","citation_count":16,"is_preprint":false},{"pmid":"33742122","id":"PMC_33742122","title":"Transmembrane and coiled-coil domain family 3 (TMCC3) regulates breast cancer stem cell and AKT activation.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/33742122","citation_count":13,"is_preprint":false},{"pmid":"27697108","id":"PMC_27697108","title":"Expression and characterization of transmembrane and coiled-coil domain family 3.","date":"2016","source":"BMB reports","url":"https://pubmed.ncbi.nlm.nih.gov/27697108","citation_count":9,"is_preprint":false},{"pmid":"31696206","id":"PMC_31696206","title":"TMCC3 localizes at the three-way junctions for the proper tubular network of the endoplasmic reticulum.","date":"2019","source":"The Biochemical 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eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/35911132","citation_count":1,"is_preprint":false},{"pmid":"41578465","id":"PMC_41578465","title":"Integrating plasma proteomes with genome-wide association data for causal protein identification in hepatocellular carcinoma: A bidirectional Mendelian randomization study.","date":"2026","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41578465","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10072,"output_tokens":1582,"usd":0.026973,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8349,"output_tokens":2207,"usd":0.04846,"stage2_stop_reason":"end_turn"},"total_usd":0.075433,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"TMCC3 protein self-assembles into oligomers and localizes to the endoplasmic reticulum through its transmembrane domains. TMCC3 associates with 14-3-3 proteins as identified by immunoprecipitation and mass spectrometry.\",\n      \"method\": \"Recombinant protein expression with deletion mutants, immunostaining, confocal microscopy, immunoprecipitation, mass spectrometry\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (subcellular localization by imaging, oligomerization by deletion mutants, binding partner by Co-IP/MS) in a single lab study\",\n      \"pmids\": [\"27697108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TMCC3 localizes specifically at three-way junctions of the peripheral ER tubular network. Its N-terminal coiled-coil domain is required for three-way junction localization. TMCC3 binds to atlastins through its C-terminal transmembrane domains, but the coiled-coil domain is required for localization independently of atlastin binding. TMCC3 knockdown reduces the number of three-way junctions and expands ER sheets, diminishing the tubular ER network; this phenotype is partially rescued by atlastin-2 overexpression, indicating TMCC3 supports atlastin activity.\",\n      \"method\": \"Transfection of TEX28 family members in U2OS cells, fluorescence microscopy, domain truncation mutants, knockdown (RNAi), overexpression rescue experiments\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (localization, domain mutagenesis, knockdown with defined phenotype, rescue epistasis) in a focused mechanistic study\",\n      \"pmids\": [\"31696206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TMCC3 directly interacts with AKT through its N-terminal 1–153 amino acid domain, as demonstrated by cell-free biochemical assay and co-immunoprecipitation with domain mapping. TMCC3 positively regulates AKT activation: TMCC3 silencing reduces AKT activation while overexpression enhances it. The AKT-interacting domain of TMCC3 is required for TMCC3-induced AKT activation, breast cancer stem cell self-renewal, and metastasis.\",\n      \"method\": \"Cell-free biochemical binding assay, co-immunoprecipitation, domain truncation/mapping, siRNA knockdown, overexpression, in vitro mammosphere and ALDH assays, in vivo xenograft and metastasis models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, cell-free binding assay, domain mapping, functional KD and OE with multiple orthogonal readouts in a single rigorous study\",\n      \"pmids\": [\"33742122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"14-3-3γ binds to the N-terminus of TMCC3 via deduced phospho-serine binding motifs and negatively regulates TMCC3 localization to ER three-way junctions. Overexpression of 14-3-3γ reduces TMCC3 at three-way junctions and decreases junction number. A TMCC3 serine-to-alanine mutant in the 14-3-3 binding motif shows reduced 14-3-3γ binding and is more resistant to 14-3-3γ-driven displacement from three-way junctions. The phosphorylation-dependent 14-3-3γ binding thus underlies remodeling of the reticular ER network.\",\n      \"method\": \"Co-immunoprecipitation, overexpression, site-directed mutagenesis (serine-to-alanine), fluorescence microscopy, TMCC3 knockdown rescue assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, structure-function mutagenesis, knockdown/rescue with defined ER morphology phenotype, multiple orthogonal methods in single focused study\",\n      \"pmids\": [\"36549645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PPARγ directly and positively regulates Tmcc3 gene transcription through a PPARγ-responsive element in the 5'-region of Tmcc3-1b and -1c isoforms, as shown by reporter assays and EMSA. Liver-specific PPARγ knockout ameliorates elevated TMCC3-1B expression in ob/ob fatty liver mice.\",\n      \"method\": \"Reporter assay, electrophoretic mobility shift assay (EMSA), liver-specific knockout mouse model, identification of three Tmcc3 exon-1 variants\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — EMSA and reporter assay establish direct PPARγ binding and transactivation; knockout confirms in vivo relevance; single lab\",\n      \"pmids\": [\"39326649\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMCC3 is an ER-resident transmembrane protein that self-oligomerizes and localizes specifically to ER tubule three-way junctions via its N-terminal coiled-coil domain, where it promotes the tubular ER network by supporting atlastin GTPase activity; its junction localization is negatively regulated by phosphorylation-dependent binding of 14-3-3γ; in cancer cells, TMCC3 also directly binds and activates AKT through its N-terminal domain to promote breast cancer stem cell self-renewal and metastasis; and its transcription is driven by PPARγ in fatty liver.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMCC3 is an endoplasmic reticulum transmembrane protein that shapes the tubular ER network by localizing specifically to ER tubule three-way junctions [#1]. It self-assembles into oligomers and is anchored in the ER through its transmembrane domains, while its N-terminal coiled-coil domain directs the protein to three-way junctions [#0, #1]. TMCC3 binds atlastin GTPases through its C-terminal transmembrane segments, and TMCC3 loss reduces three-way junctions and expands ER sheets—a phenotype partially rescued by atlastin-2 overexpression, establishing that TMCC3 supports atlastin activity in promoting the reticular ER [#1]. Junction localization is negatively regulated by phosphorylation-dependent binding of 14-3-3\\u03b3 to the TMCC3 N-terminus, which displaces TMCC3 from three-way junctions and remodels the ER network [#3]. Beyond ER morphogenesis, TMCC3 directly binds AKT via its N-terminal 1\\u2013153 residue domain and positively regulates AKT activation, and this interaction drives breast cancer stem cell self-renewal and metastasis [#2]. TMCC3 transcription is directly activated by PPAR\\u03b3 through a responsive element in its 5' region, accounting for elevated expression in fatty liver [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Establishing where TMCC3 resides and how it is organized was the first step in defining its cellular role, showing it is an ER-anchored protein that oligomerizes and engages 14-3-3 proteins.\",\n      \"evidence\": \"Deletion-mutant expression, confocal immunostaining, and immunoprecipitation/mass spectrometry of recombinant TMCC3\",\n      \"pmids\": [\"27697108\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The functional consequence of oligomerization was not defined\", \"The specific 14-3-3 isoform and the regulatory role of the interaction were not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"This work resolved the molecular function of TMCC3 in ER architecture, demonstrating that it concentrates at three-way junctions via its coiled-coil domain and supports atlastin-driven formation of the tubular ER network.\",\n      \"evidence\": \"Domain-truncation mapping, fluorescence microscopy, RNAi knockdown with defined ER-morphology phenotype, and atlastin-2 overexpression rescue in U2OS cells\",\n      \"pmids\": [\"31696206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The biochemical mechanism by which TMCC3 enhances atlastin GTPase activity was not determined\", \"Whether junction targeting is dynamically regulated was not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"An unexpected signaling function was uncovered, showing TMCC3 directly binds and activates AKT to drive breast cancer stem cell self-renewal and metastasis—linking the ER protein to oncogenic signaling.\",\n      \"evidence\": \"Cell-free binding assay, reciprocal Co-IP with domain mapping, siRNA/overexpression, mammosphere and ALDH assays, and xenograft/metastasis models\",\n      \"pmids\": [\"33742122\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How an ER membrane protein engages cytosolic AKT mechanistically was not resolved\", \"Whether AKT activation is connected to TMCC3's ER junction role is unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The regulatory logic of TMCC3 junction localization was defined, showing phosphorylation-dependent 14-3-3\\u03b3 binding to the N-terminus displaces TMCC3 from three-way junctions and remodels the ER network.\",\n      \"evidence\": \"Reciprocal Co-IP, serine-to-alanine site-directed mutagenesis, overexpression, and knockdown/rescue with ER-morphology readout\",\n      \"pmids\": [\"36549645\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The kinase that phosphorylates the 14-3-3 binding motif was not identified\", \"The physiological signal triggering 14-3-3\\u03b3-mediated remodeling was not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Transcriptional control of TMCC3 was established, identifying PPAR\\u03b3 as a direct activator of Tmcc3 isoforms and linking its upregulation to fatty liver.\",\n      \"evidence\": \"Reporter assays, EMSA, identification of exon-1 variants, and liver-specific PPAR\\u03b3 knockout in ob/ob mice\",\n      \"pmids\": [\"39326649\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The functional role of elevated TMCC3 in hepatic lipid metabolism was not established\", \"Whether the ER or AKT functions mediate the fatty-liver phenotype is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TMCC3's distinct activities—ER three-way junction organization, atlastin support, and direct AKT activation—are mechanistically integrated within one protein remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model connecting the coiled-coil, AKT-binding, and transmembrane regions\", \"Whether ER architecture and AKT signaling functions are coupled is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ATL2\", \"AKT1\", \"YWHAG\", \"PPARG\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}