{"gene":"TANC1","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2008,"finding":"MINK (Misshapen/NIKs-related kinase) is a Rap2 effector that interacts with TANC1 in a GTP-dependent manner and phosphorylates TANC1 in cultured cells. TNIK (Traf2- and Nck-interacting kinase) also interacts with TANC1 and induces its phosphorylation. The MINK–TANC1 interaction is under control of Rap2 signaling.","method":"Affinity chromatography/mass spectrometry, yeast two-hybrid, co-immunoprecipitation, and phosphorylation assays in cultured cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction shown by multiple methods (affinity chromatography, yeast two-hybrid, co-IP, phosphorylation assay) in a single lab","pmids":["18930710"],"is_preprint":false},{"year":2010,"finding":"TANC1 interacts with PSD-95 via its PDZ-binding C-terminus. Overexpression of TANC1 in cultured neurons increases dendritic spine density and excitatory synapse number in a manner requiring the C-terminal PDZ-binding motif. TANC1-deficient mice show reduced spine density specifically in the CA3 region of the hippocampus and impaired spatial memory.","method":"Overexpression and dominant-negative experiments in cultured neurons, TANC1 knockout mouse analysis (spine morphometry, behavioral testing), interaction demonstrated by PDZ-binding C-terminus requirement","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function mouse with defined cellular and behavioral phenotype, gain-of-function in neurons with domain-mapping, independently consistent across multiple readouts","pmids":["21068316"],"is_preprint":false},{"year":2011,"finding":"TANC1 (ortholog of Drosophila rolling pebbles/rols) is essential for myoblast fusion but dispensable for terminal differentiation. PAX-FOXO1 upregulates TANC1 expression, blocking differentiation; RNAi-mediated reduction of TANC1 to native levels restores both fusion and differentiation. Reducing TANC1 expression in RMS cancer cells caused them to lose neoplastic state, undergo fusion, and form differentiated syncytial muscle.","method":"RNAi gene silencing in mammalian myoblasts, Drosophila genetic epistasis (rols mutation suppresses PAX-FOXO1 lethality), PAX-FOXO1 overexpression combined with TANC1 RNAi rescue","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis in Drosophila model validated by mammalian RNAi with specific cellular rescue phenotype, multiple orthogonal approaches in one study","pmids":["22182840"],"is_preprint":false},{"year":2019,"finding":"The TANC1 ankyrin repeat (AR) domain was expressed, purified, and biochemically characterized. The domain lacks canonical N- and C-capping units, causing low solubility and instability. Introducing point mutations at the C-capping unit and replacing the N-capping unit yielded a monomeric, well-folded protein. Disease-associated missense mutations from intellectual disability patients showed marginal effects on conformation and stability of the AR domain, whereas cancer-associated mutations dramatically decreased solubility, suggesting these variants may disrupt protein folding or interactions mediated by the AR domain.","method":"Recombinant protein expression and purification, SEC-MALS, circular dichroism spectroscopy, site-directed mutagenesis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical characterization with mutagenesis and biophysical methods in a single lab","pmids":["31040020"],"is_preprint":false},{"year":2021,"finding":"TANC1 harbors a C-terminal PDZ-binding motif (PDZBM). Using immunopurification and peptide-based affinity purification followed by mass spectrometry, several PDZ domain-containing proteins were identified as interaction partners of TANC1 via its PDZBM.","method":"Immunopurification, peptide-based affinity purification, mass spectrometry","journal":"Methods in molecular biology (Clifton, N.J.)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single pulldown/AP-MS approach, single lab, partners not individually validated by orthogonal methods in this study","pmids":["34014514"],"is_preprint":false},{"year":2023,"finding":"TANC1 TPR domain directly interacts with the coiled-coil domain and C-extension (CCex) of Myo18a, mediated primarily by charge-charge interactions (disrupted by high salt). The TANC1-TPR/Myo18a-CCex complex undergoes liquid-liquid phase separation (LLPS) in both test tubes and cultured cells.","method":"Size exclusion chromatography, high-salt disruption experiments, LLPS assays in vitro and in cultured cells","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction characterized by SEC and salt-disruption, LLPS validated in vitro and in cells, single lab with two orthogonal systems","pmids":["38092135"],"is_preprint":false},{"year":2026,"finding":"Cryo-EM structures of mouse Tanc1 (residues 215-1452) and Tanc2 (residues 211-1421) revealed that both are STAND/NACHT ATPases. Tanc1 adopts a closed, inactive (autoinhibited) conformation stabilized by a '226-231 lock' segment. Tanc2 dynamically switches between closed and pre-activated states and undergoes ATP-dependent oligomerization with ATPase activity and cytoplasmic puncta formation. Neurodevelopmental disorder-associated Tanc2 mutations (R755H, A794V, C890R) enhanced oligomerization, elevated ATPase activity, and triggered apoptosis, indicating a hyperactivation-driven pathogenic mechanism.","method":"Cryo-EM structure determination, biochemical ATPase assays, cellular oligomerization and puncta assays, disease-mutation mutagenesis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure combined with biochemical ATPase assays, mutagenesis, and cellular functional assays in one rigorous study","pmids":["42035792"],"is_preprint":false}],"current_model":"TANC1 is a postsynaptic scaffold protein and STAND/NACHT ATPase that adopts an autoinhibited closed conformation stabilized by a 'lock' segment; it interacts with PSD-95 via its C-terminal PDZ-binding motif, with Myo18a via its TPR domain (forming liquid-liquid phase separation condensates), and is phosphorylated by the Rap2 effector kinase MINK/TNIK; in neurons it promotes dendritic spine maintenance and excitatory synapse strength, and in myoblasts it is essential for cell fusion downstream of PAX-FOXO1 signaling."},"narrative":{"mechanistic_narrative":"TANC1 is a multidomain scaffold protein that organizes excitatory postsynaptic signaling and also controls myoblast fusion as a developmental switch [PMID:21068316, PMID:22182840]. At the synapse, TANC1 binds PSD-95 through its C-terminal PDZ-binding motif, and its overexpression drives dendritic spine formation and increases excitatory synapse number in a manner that depends on this motif; loss of TANC1 in mice reduces CA3 hippocampal spine density and impairs spatial memory [PMID:21068316]. The same PDZ-binding motif recruits additional PDZ-domain proteins, extending TANC1's role as a postsynaptic organizer [PMID:34014514]. TANC1 is a target of Rap2 signaling: it is bound and phosphorylated by the Rap2 effector kinases MINK and TNIK, the MINK interaction being GTP-dependent [PMID:18930710]. Through its TPR domain TANC1 engages the coiled-coil/C-extension region of Myo18a via charge-based contacts, and this complex drives liquid-liquid phase separation in vitro and in cells, providing a mechanism for condensing scaffold assemblies [PMID:38092135]. Structurally, TANC1 is a STAND/NACHT ATPase that rests in a closed, autoinhibited conformation stabilized by a '226-231 lock' segment, contrasting with its paralog Tanc2, whose disease mutations cause ATPase hyperactivation [PMID:42035792]. Independently of its neuronal role, TANC1 is upregulated by PAX-FOXO1 to block differentiation while being essential for myoblast fusion; reducing TANC1 in rhabdomyosarcoma cells reverses the neoplastic state and restores syncytial muscle formation [PMID:22182840]. Disease-associated missense variants in the ankyrin-repeat domain have been characterized biochemically, with cancer-associated mutations strongly destabilizing the domain [PMID:31040020].","teleology":[{"year":2008,"claim":"Established that TANC1 is a downstream node of Rap2 signaling by identifying it as a substrate of the GTP-regulated effector kinases MINK and TNIK, placing TANC1 within a defined small-GTPase signaling cascade.","evidence":"Affinity chromatography/MS, yeast two-hybrid, co-IP, and phosphorylation assays in cultured cells","pmids":["18930710"],"confidence":"Medium","gaps":["Functional consequence of TANC1 phosphorylation not defined","Phosphosites not mapped","Single-lab characterization"]},{"year":2010,"claim":"Defined TANC1 as a postsynaptic scaffold that promotes dendritic spine and excitatory synapse formation through its PDZ-binding motif binding PSD-95, with knockout mice linking this to hippocampal spine density and spatial memory.","evidence":"Neuronal overexpression/dominant-negative experiments, TANC1 knockout mouse spine morphometry and behavior, PDZ-motif domain mapping","pmids":["21068316"],"confidence":"High","gaps":["Whether PSD-95 binding fully accounts for the spine phenotype not resolved","Region specificity (CA3) mechanism unexplained","Molecular mechanism of spine maintenance not detailed"]},{"year":2011,"claim":"Revealed a non-neuronal role for TANC1 as a PAX-FOXO1-induced differentiation block essential for myoblast fusion, with direct relevance to rhabdomyosarcoma where its reduction restores muscle differentiation.","evidence":"Mammalian myoblast RNAi, Drosophila rols genetic epistasis, PAX-FOXO1 overexpression with TANC1 RNAi rescue","pmids":["22182840"],"confidence":"High","gaps":["Molecular fusion machinery engaged by TANC1 not identified","How a synaptic scaffold operates in fusion mechanistically unclear","Direct PAX-FOXO1 transcriptional regulation of TANC1 not dissected"]},{"year":2019,"claim":"Provided biochemical characterization of the ankyrin-repeat domain and showed that disease variants differ in impact, with cancer-associated mutations destabilizing the fold while intellectual-disability variants had marginal effects.","evidence":"Recombinant protein purification, SEC-MALS, circular dichroism, site-directed mutagenesis","pmids":["31040020"],"confidence":"Medium","gaps":["Functional/binding consequences of destabilization not tested in cells","Engineered capping units differ from native protein","Partners mediated by the AR domain not identified"]},{"year":2021,"claim":"Extended the TANC1 interactome by identifying multiple PDZ-domain proteins captured through its C-terminal PDZ-binding motif, broadening its scaffolding repertoire beyond PSD-95.","evidence":"Immunopurification and peptide-based affinity purification with mass spectrometry","pmids":["34014514"],"confidence":"Low","gaps":["Single AP-MS approach without orthogonal validation of individual partners","Functional relevance of new partners untested","Cellular context of interactions undefined"]},{"year":2023,"claim":"Identified a direct TPR-domain interaction with Myo18a and demonstrated that the complex undergoes liquid-liquid phase separation, providing a biophysical mechanism for TANC1-driven condensate assembly.","evidence":"Size exclusion chromatography, high-salt disruption, LLPS assays in vitro and in cultured cells","pmids":["38092135"],"confidence":"Medium","gaps":["Physiological role of TANC1-Myo18a condensates not established in neurons","Regulation of LLPS not defined","Single-lab characterization"]},{"year":2026,"claim":"Resolved TANC1 as a STAND/NACHT ATPase held in an autoinhibited closed state by a '226-231 lock', defining a structural/enzymatic basis for the protein and contrasting it with hyperactivating disease mutations in its paralog Tanc2.","evidence":"Cryo-EM structure determination, ATPase assays, cellular oligomerization/puncta assays, disease-mutation mutagenesis","pmids":["42035792"],"confidence":"High","gaps":["Conditions that release TANC1 autoinhibition not identified","Whether TANC1 (vs Tanc2) oligomerizes/has ATPase activity in vivo unclear","Link between ATPase state and synaptic scaffolding function unestablished"]},{"year":null,"claim":"How TANC1's STAND/NACHT ATPase conformational switching is coupled to its scaffolding functions at synapses and in myoblast fusion, and what signals release its autoinhibited state, remain unknown.","evidence":"","pmids":[],"confidence":"High","gaps":["No physiological activator of TANC1 ATPase identified","Integration of Rap2/MINK phosphorylation with conformational state untested","Mechanistic unity of synaptic vs myogenic roles unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,4,5]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2]}],"complexes":[],"partners":["PSD-95","MINK","TNIK","MYO18A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9C0D5","full_name":"Protein TANC1","aliases":["Tetratricopeptide repeat, ankyrin repeat and coiled-coil domain-containing protein 1"],"length_aa":1861,"mass_kda":202.2,"function":"May be a scaffold component in the postsynaptic density","subcellular_location":"Postsynaptic density","url":"https://www.uniprot.org/uniprotkb/Q9C0D5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TANC1","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":"AGAP1","stoichiometry":0.2},{"gene":"AGAP3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TANC1","total_profiled":1310},"omim":[{"mim_id":"615047","title":"TETRATRICOPEPTIDE REPEAT-, ANKYRIN REPEAT-, AND COILED-COIL-CONTAINING PROTEIN 2; TANC2","url":"https://www.omim.org/entry/615047"},{"mim_id":"611397","title":"TETRATRICOPEPTIDE REPEAT-, ANKYRIN REPEAT-, AND COILED-COIL-CONTAINING PROTEIN 1; TANC1","url":"https://www.omim.org/entry/611397"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TANC1"},"hgnc":{"alias_symbol":["KIAA1728","ROLSB"],"prev_symbol":[]},"alphafold":{"accession":"Q9C0D5","domains":[{"cath_id":"3.40.50.300","chopping":"366-442_490-649","consensus_level":"medium","plddt":86.6246,"start":366,"end":649},{"cath_id":"-","chopping":"652-731","consensus_level":"medium","plddt":87.339,"start":652,"end":731},{"cath_id":"-","chopping":"733-843","consensus_level":"medium","plddt":90.5471,"start":733,"end":843},{"cath_id":"1.25.40.20","chopping":"1138-1270","consensus_level":"medium","plddt":90.7985,"start":1138,"end":1270}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C0D5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C0D5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C0D5-F1-predicted_aligned_error_v6.png","plddt_mean":61.28},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TANC1","jax_strain_url":"https://www.jax.org/strain/search?query=TANC1"},"sequence":{"accession":"Q9C0D5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9C0D5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9C0D5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C0D5"}},"corpus_meta":[{"pmid":"24974847","id":"PMC_24974847","title":"A three-stage genome-wide association study identifies a susceptibility locus for late radiotherapy toxicity at 2q24.1.","date":"2014","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24974847","citation_count":119,"is_preprint":false},{"pmid":"21068316","id":"PMC_21068316","title":"Regulation of dendritic spines, spatial memory, and embryonic development by the TANC family of PSD-95-interacting proteins.","date":"2010","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/21068316","citation_count":61,"is_preprint":false},{"pmid":"18930710","id":"PMC_18930710","title":"MINK is a Rap2 effector for phosphorylation of the postsynaptic scaffold protein TANC1.","date":"2008","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/18930710","citation_count":37,"is_preprint":false},{"pmid":"22069443","id":"PMC_22069443","title":"Putting into practice domain-linear motif interaction predictions for exploration of protein networks.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22069443","citation_count":34,"is_preprint":false},{"pmid":"22182840","id":"PMC_22182840","title":"Drosophila and mammalian models uncover a role for the myoblast fusion gene TANC1 in rhabdomyosarcoma.","date":"2011","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/22182840","citation_count":25,"is_preprint":false},{"pmid":"28754924","id":"PMC_28754924","title":"Dynamic scaffolds for neuronal signaling: in silico analysis of the TANC protein family.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28754924","citation_count":25,"is_preprint":false},{"pmid":"29070031","id":"PMC_29070031","title":"17q23.2q23.3 de novo duplication in association with speech and language disorder, learning difficulties, incoordination, motor skill impairment, and behavioral disturbances: a case report.","date":"2017","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29070031","citation_count":10,"is_preprint":false},{"pmid":"21739571","id":"PMC_21739571","title":"Complex chromosomal rearrangement in a girl with psychomotor-retardation and a de novo inversion: inv(2)(p15;q24.2).","date":"2011","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/21739571","citation_count":9,"is_preprint":false},{"pmid":"34465797","id":"PMC_34465797","title":"TANC1 methylation as a novel biomarker for the diagnosis of patients with anti-tuberculosis drug-induced liver injury.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34465797","citation_count":8,"is_preprint":false},{"pmid":"38935197","id":"PMC_38935197","title":"Pure Apocrine Intraductal Carcinoma of Salivary Glands: Reassessment of Molecular Underpinnings and Behavior.","date":"2024","source":"Head and neck pathology","url":"https://pubmed.ncbi.nlm.nih.gov/38935197","citation_count":8,"is_preprint":false},{"pmid":"31040020","id":"PMC_31040020","title":"Purification and mutagenesis studies of TANC1 ankyrin repeats domain provide clues to understand mis-sense variants from diseases.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/31040020","citation_count":7,"is_preprint":false},{"pmid":"35620462","id":"PMC_35620462","title":"Association of a Novel DOCK2 Mutation-Related Gene Signature With Immune in Hepatocellular Carcinoma.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35620462","citation_count":5,"is_preprint":false},{"pmid":"39273703","id":"PMC_39273703","title":"GWAS Enhances Genomic Prediction Accuracy of Caviar Yield, Caviar Color and Body Weight Traits in Sturgeons Using Whole-Genome Sequencing Data.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39273703","citation_count":5,"is_preprint":false},{"pmid":"38923999","id":"PMC_38923999","title":"Quantitative proteomics analysis reveals possible anticancer mechanisms of 5'-deoxy-5'-methylthioadenosine in cholangiocarcinoma cells.","date":"2024","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/38923999","citation_count":4,"is_preprint":false},{"pmid":"39696495","id":"PMC_39696495","title":"Epigenetic regulation on left atrial function and disease recurrence after catheter ablation in atrial fibrillation.","date":"2024","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/39696495","citation_count":4,"is_preprint":false},{"pmid":"38092135","id":"PMC_38092135","title":"Tanc1/2 TPR domain interacts with Myo18a C-terminus and undergoes liquid-liquid phase separation.","date":"2023","source":"Biochimica et biophysica acta. 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TNIK (Traf2- and Nck-interacting kinase) also interacts with TANC1 and induces its phosphorylation. The MINK–TANC1 interaction is under control of Rap2 signaling.\",\n      \"method\": \"Affinity chromatography/mass spectrometry, yeast two-hybrid, co-immunoprecipitation, and phosphorylation assays in cultured cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction shown by multiple methods (affinity chromatography, yeast two-hybrid, co-IP, phosphorylation assay) in a single lab\",\n      \"pmids\": [\"18930710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TANC1 interacts with PSD-95 via its PDZ-binding C-terminus. Overexpression of TANC1 in cultured neurons increases dendritic spine density and excitatory synapse number in a manner requiring the C-terminal PDZ-binding motif. TANC1-deficient mice show reduced spine density specifically in the CA3 region of the hippocampus and impaired spatial memory.\",\n      \"method\": \"Overexpression and dominant-negative experiments in cultured neurons, TANC1 knockout mouse analysis (spine morphometry, behavioral testing), interaction demonstrated by PDZ-binding C-terminus requirement\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function mouse with defined cellular and behavioral phenotype, gain-of-function in neurons with domain-mapping, independently consistent across multiple readouts\",\n      \"pmids\": [\"21068316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TANC1 (ortholog of Drosophila rolling pebbles/rols) is essential for myoblast fusion but dispensable for terminal differentiation. PAX-FOXO1 upregulates TANC1 expression, blocking differentiation; RNAi-mediated reduction of TANC1 to native levels restores both fusion and differentiation. Reducing TANC1 expression in RMS cancer cells caused them to lose neoplastic state, undergo fusion, and form differentiated syncytial muscle.\",\n      \"method\": \"RNAi gene silencing in mammalian myoblasts, Drosophila genetic epistasis (rols mutation suppresses PAX-FOXO1 lethality), PAX-FOXO1 overexpression combined with TANC1 RNAi rescue\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis in Drosophila model validated by mammalian RNAi with specific cellular rescue phenotype, multiple orthogonal approaches in one study\",\n      \"pmids\": [\"22182840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The TANC1 ankyrin repeat (AR) domain was expressed, purified, and biochemically characterized. The domain lacks canonical N- and C-capping units, causing low solubility and instability. Introducing point mutations at the C-capping unit and replacing the N-capping unit yielded a monomeric, well-folded protein. Disease-associated missense mutations from intellectual disability patients showed marginal effects on conformation and stability of the AR domain, whereas cancer-associated mutations dramatically decreased solubility, suggesting these variants may disrupt protein folding or interactions mediated by the AR domain.\",\n      \"method\": \"Recombinant protein expression and purification, SEC-MALS, circular dichroism spectroscopy, site-directed mutagenesis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical characterization with mutagenesis and biophysical methods in a single lab\",\n      \"pmids\": [\"31040020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TANC1 harbors a C-terminal PDZ-binding motif (PDZBM). Using immunopurification and peptide-based affinity purification followed by mass spectrometry, several PDZ domain-containing proteins were identified as interaction partners of TANC1 via its PDZBM.\",\n      \"method\": \"Immunopurification, peptide-based affinity purification, mass spectrometry\",\n      \"journal\": \"Methods in molecular biology (Clifton, N.J.)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single pulldown/AP-MS approach, single lab, partners not individually validated by orthogonal methods in this study\",\n      \"pmids\": [\"34014514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TANC1 TPR domain directly interacts with the coiled-coil domain and C-extension (CCex) of Myo18a, mediated primarily by charge-charge interactions (disrupted by high salt). The TANC1-TPR/Myo18a-CCex complex undergoes liquid-liquid phase separation (LLPS) in both test tubes and cultured cells.\",\n      \"method\": \"Size exclusion chromatography, high-salt disruption experiments, LLPS assays in vitro and in cultured cells\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction characterized by SEC and salt-disruption, LLPS validated in vitro and in cells, single lab with two orthogonal systems\",\n      \"pmids\": [\"38092135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Cryo-EM structures of mouse Tanc1 (residues 215-1452) and Tanc2 (residues 211-1421) revealed that both are STAND/NACHT ATPases. Tanc1 adopts a closed, inactive (autoinhibited) conformation stabilized by a '226-231 lock' segment. Tanc2 dynamically switches between closed and pre-activated states and undergoes ATP-dependent oligomerization with ATPase activity and cytoplasmic puncta formation. Neurodevelopmental disorder-associated Tanc2 mutations (R755H, A794V, C890R) enhanced oligomerization, elevated ATPase activity, and triggered apoptosis, indicating a hyperactivation-driven pathogenic mechanism.\",\n      \"method\": \"Cryo-EM structure determination, biochemical ATPase assays, cellular oligomerization and puncta assays, disease-mutation mutagenesis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure combined with biochemical ATPase assays, mutagenesis, and cellular functional assays in one rigorous study\",\n      \"pmids\": [\"42035792\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TANC1 is a postsynaptic scaffold protein and STAND/NACHT ATPase that adopts an autoinhibited closed conformation stabilized by a 'lock' segment; it interacts with PSD-95 via its C-terminal PDZ-binding motif, with Myo18a via its TPR domain (forming liquid-liquid phase separation condensates), and is phosphorylated by the Rap2 effector kinase MINK/TNIK; in neurons it promotes dendritic spine maintenance and excitatory synapse strength, and in myoblasts it is essential for cell fusion downstream of PAX-FOXO1 signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TANC1 is a multidomain scaffold protein that organizes excitatory postsynaptic signaling and also controls myoblast fusion as a developmental switch [#1, #2]. At the synapse, TANC1 binds PSD-95 through its C-terminal PDZ-binding motif, and its overexpression drives dendritic spine formation and increases excitatory synapse number in a manner that depends on this motif; loss of TANC1 in mice reduces CA3 hippocampal spine density and impairs spatial memory [#1]. The same PDZ-binding motif recruits additional PDZ-domain proteins, extending TANC1's role as a postsynaptic organizer [#4]. TANC1 is a target of Rap2 signaling: it is bound and phosphorylated by the Rap2 effector kinases MINK and TNIK, the MINK interaction being GTP-dependent [#0]. Through its TPR domain TANC1 engages the coiled-coil/C-extension region of Myo18a via charge-based contacts, and this complex drives liquid-liquid phase separation in vitro and in cells, providing a mechanism for condensing scaffold assemblies [#5]. Structurally, TANC1 is a STAND/NACHT ATPase that rests in a closed, autoinhibited conformation stabilized by a '226-231 lock' segment, contrasting with its paralog Tanc2, whose disease mutations cause ATPase hyperactivation [#6]. Independently of its neuronal role, TANC1 is upregulated by PAX-FOXO1 to block differentiation while being essential for myoblast fusion; reducing TANC1 in rhabdomyosarcoma cells reverses the neoplastic state and restores syncytial muscle formation [#2]. Disease-associated missense variants in the ankyrin-repeat domain have been characterized biochemically, with cancer-associated mutations strongly destabilizing the domain [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that TANC1 is a downstream node of Rap2 signaling by identifying it as a substrate of the GTP-regulated effector kinases MINK and TNIK, placing TANC1 within a defined small-GTPase signaling cascade.\",\n      \"evidence\": \"Affinity chromatography/MS, yeast two-hybrid, co-IP, and phosphorylation assays in cultured cells\",\n      \"pmids\": [\"18930710\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of TANC1 phosphorylation not defined\", \"Phosphosites not mapped\", \"Single-lab characterization\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined TANC1 as a postsynaptic scaffold that promotes dendritic spine and excitatory synapse formation through its PDZ-binding motif binding PSD-95, with knockout mice linking this to hippocampal spine density and spatial memory.\",\n      \"evidence\": \"Neuronal overexpression/dominant-negative experiments, TANC1 knockout mouse spine morphometry and behavior, PDZ-motif domain mapping\",\n      \"pmids\": [\"21068316\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PSD-95 binding fully accounts for the spine phenotype not resolved\", \"Region specificity (CA3) mechanism unexplained\", \"Molecular mechanism of spine maintenance not detailed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed a non-neuronal role for TANC1 as a PAX-FOXO1-induced differentiation block essential for myoblast fusion, with direct relevance to rhabdomyosarcoma where its reduction restores muscle differentiation.\",\n      \"evidence\": \"Mammalian myoblast RNAi, Drosophila rols genetic epistasis, PAX-FOXO1 overexpression with TANC1 RNAi rescue\",\n      \"pmids\": [\"22182840\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular fusion machinery engaged by TANC1 not identified\", \"How a synaptic scaffold operates in fusion mechanistically unclear\", \"Direct PAX-FOXO1 transcriptional regulation of TANC1 not dissected\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided biochemical characterization of the ankyrin-repeat domain and showed that disease variants differ in impact, with cancer-associated mutations destabilizing the fold while intellectual-disability variants had marginal effects.\",\n      \"evidence\": \"Recombinant protein purification, SEC-MALS, circular dichroism, site-directed mutagenesis\",\n      \"pmids\": [\"31040020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional/binding consequences of destabilization not tested in cells\", \"Engineered capping units differ from native protein\", \"Partners mediated by the AR domain not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended the TANC1 interactome by identifying multiple PDZ-domain proteins captured through its C-terminal PDZ-binding motif, broadening its scaffolding repertoire beyond PSD-95.\",\n      \"evidence\": \"Immunopurification and peptide-based affinity purification with mass spectrometry\",\n      \"pmids\": [\"34014514\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single AP-MS approach without orthogonal validation of individual partners\", \"Functional relevance of new partners untested\", \"Cellular context of interactions undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a direct TPR-domain interaction with Myo18a and demonstrated that the complex undergoes liquid-liquid phase separation, providing a biophysical mechanism for TANC1-driven condensate assembly.\",\n      \"evidence\": \"Size exclusion chromatography, high-salt disruption, LLPS assays in vitro and in cultured cells\",\n      \"pmids\": [\"38092135\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological role of TANC1-Myo18a condensates not established in neurons\", \"Regulation of LLPS not defined\", \"Single-lab characterization\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved TANC1 as a STAND/NACHT ATPase held in an autoinhibited closed state by a '226-231 lock', defining a structural/enzymatic basis for the protein and contrasting it with hyperactivating disease mutations in its paralog Tanc2.\",\n      \"evidence\": \"Cryo-EM structure determination, ATPase assays, cellular oligomerization/puncta assays, disease-mutation mutagenesis\",\n      \"pmids\": [\"42035792\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conditions that release TANC1 autoinhibition not identified\", \"Whether TANC1 (vs Tanc2) oligomerizes/has ATPase activity in vivo unclear\", \"Link between ATPase state and synaptic scaffolding function unestablished\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TANC1's STAND/NACHT ATPase conformational switching is coupled to its scaffolding functions at synapses and in myoblast fusion, and what signals release its autoinhibited state, remain unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No physiological activator of TANC1 ATPase identified\", \"Integration of Rap2/MINK phosphorylation with conformational state untested\", \"Mechanistic unity of synaptic vs myogenic roles unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 4, 5]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PSD-95\", \"MINK\", \"TNIK\", \"Myo18a\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":8,"faith_total":8,"faith_pct":100.0}}