{"gene":"TMCO1","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2016,"finding":"TMCO1 is an ER transmembrane protein that forms a Ca2+-selective ion channel ('Ca2+ load-activated Ca2+ channel', CLAC) on giant liposomes and undergoes reversible homotetramerization in response to ER Ca2+ overloading, dissociating upon Ca2+ depletion, thereby preventing ER Ca2+ overfilling.","method":"Giant liposome electrophysiology, co-immunoprecipitation of oligomeric complexes, TMCO1 knockout mouse model with ER Ca2+ measurement, in vitro reconstitution","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted ion channel activity in giant liposomes, biochemical characterization of homotetramerization, KO mouse phenotype, multiple orthogonal methods in single rigorous study","pmids":["27212239"],"is_preprint":false},{"year":2020,"finding":"TMCO1 protein from Dictyostelium discoideum (ortholog) contains three α-helical transmembrane regions as determined by solution NMR in DPC micelles; recombinant protein was successfully purified by affinity and size exclusion chromatography.","method":"Solution NMR spectroscopy in DPC micelles, recombinant protein expression and purification (E. coli and insect cells)","journal":"Protein expression and purification","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — NMR structural characterization in a non-mammalian ortholog, single lab, no mutagenesis or functional validation reported in abstract","pmids":["33253810"],"is_preprint":false},{"year":2018,"finding":"TMCO1 is essential for ovarian follicle development; its ablation in granulosa cells causes supernormal Ca2+ signaling, ER stress-mediated apoptosis, and elevated ROS, while ER Ca2+ stores in oocytes remain normal, placing TMCO1 specifically in granulosa cell Ca2+ homeostasis.","method":"Tmco1-/- knockout mice, Ca2+ imaging in granulosa cells, RNA-sequencing, ER stress and ROS assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with specific cellular Ca2+ phenotype, multiple orthogonal readouts (Ca2+ imaging, ROS, ER stress markers, RNA-seq), single lab","pmids":["29467381"],"is_preprint":false},{"year":2022,"finding":"TMCO1 is a substrate of the ER-associated degradation E3 ubiquitin ligase Gp78, which ubiquitinates TMCO1 at K186 to promote its degradation. The oncoprotein iASPP competitively binds Gp78, interfering with Gp78-mediated TMCO1 ubiquitination and thus stabilizing TMCO1 protein levels and reducing ER Ca2+ stores.","method":"Co-immunoprecipitation, ubiquitination assays, competitive binding assay, Ca2+ store measurements, in vitro and in vivo tumor models","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP identifying specific ubiquitination site (K186), competitive binding mechanism, functional Ca2+ readout, in vivo validation, multiple orthogonal methods","pmids":["35121659"],"is_preprint":false},{"year":2022,"finding":"TMCO1 is required for normal corpus callosum development; TMCO1 deficiency causes excessive ER Ca2+ release leading to upregulation of FGFs, over-activation of ERK signaling, excess midline glial cell migration, and overproduction of Slit2, which repels neural fiber bundles from crossing the midline. Pharmacological MEK inhibition rescues corpus callosum formation in Tmco1-/- mice.","method":"Tmco1-/- knockout mice, ERK phosphorylation assays, FGF/Slit2 expression analysis, MEK inhibitor rescue experiments, brain histology","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined cellular phenotype, mechanistic pathway delineation via epistasis (MEK inhibitor rescue), multiple molecular readouts (ERK, FGFs, Slit2), single lab","pmids":["35927240"],"is_preprint":false},{"year":2019,"finding":"In TMCO1-deficient cells, ER stress causes ERAD-mediated degradation of diacylglycerol acyltransferase 2 (DGAT2), reducing triglyceride synthesis, causing non-esterified fatty acid accumulation, and resulting in decreased mitochondrial volume, enhanced mitophagy, and impaired oxidative phosphorylation.","method":"Tmco1-/- cells, lipid droplet quantification, triglyceride measurement, DGAT2 protein level analysis, mitochondrial morphology and function assays (OXPHOS)","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO cells with specific molecular pathway (ERAD of DGAT2), multiple metabolic readouts, single lab, no direct reconstitution","pmids":["30929916"],"is_preprint":false},{"year":2024,"finding":"TMCO1 promotes ferroptosis and ECM deposition in trabecular meshwork cells through ERK1/2 signaling; dexamethasone stimulation upregulates TMCO1, and ferroptosis inhibitor ferrostatin-1 reduces both ECM deposition and ferroptosis downstream of TMCO1.","method":"In vivo glaucoma model, HTM cell culture, dexamethasone stimulation, ferrostatin-1 treatment, ERK1/2 phosphorylation assays, ECM marker quantification","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo and in vitro models with pathway placement (ERK/MAPK), but single lab and abstract-level detail limits mechanistic granularity","pmids":["39343416"],"is_preprint":false},{"year":2024,"finding":"TMCO1 regulates mitochondrial function in hepatocellular carcinoma cells via TOMM20; TMCO1 overexpression promotes ATP production, increases mitochondrial membrane potential, and inhibits mPTP opening and ROS, while TOMM20 knockdown blocks these TMCO1-mediated effects, placing TOMM20 epistatically downstream of TMCO1.","method":"TMCO1 overexpression and knockdown, TOMM20 knockdown epistasis, ROS assay, mPTP assay, MMP assay, ATP measurement, subcutaneous xenograft mouse model","journal":"Biochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — epistatic genetic rescue (TOMM20 KD blocks TMCO1 effects), multiple mitochondrial readouts, single lab","pmids":["39566034"],"is_preprint":false},{"year":2024,"finding":"TMCO1 interacts with CALR (calreticulin) in ovarian cancer cells; TMCO1 overexpression upregulates CALR and VDAC1 and elevates intracellular Ca2+, while TMCO1 knockout reduces CALR and VDAC1 expression and reverses the pro-metastatic effects of CALR recombinant protein.","method":"TMCO1 overexpression and knockout, CALR/VDAC1 knockdown epistasis, Fluo-4 Ca2+ assay, ER/mitochondrial fluorescent probes, Transwell assay, Western blot, xenograft mouse model","journal":"Cellular and molecular biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/epistasis approach inferred from abstract, functional readouts present but limited mechanistic resolution on direct binding","pmids":["38372107"],"is_preprint":false},{"year":2024,"finding":"In breast cancer cells, TMCO1 interacting proteins include ER-resident Ca2+-regulatory proteins and nuclear transport proteins; TMCO1 localizes to both the nucleus and ER in MDA-MB-231 cells, and TMCO1 regulates sensitivity to BCL-2/MCL-1 inhibitors analogously to IP3 receptors.","method":"Interactome pulldown/MS for TMCO1 binding partners, immunofluorescence for localization, cell viability assays with BCL-2/MCL-1 inhibitors","journal":"Cell death discovery","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single pulldown/MS for interactors, localization by immunofluorescence without deep functional validation, single lab","pmids":["39353922"],"is_preprint":false},{"year":2012,"finding":"In human ocular tissues, endogenous TMCO1 protein localizes to the cytoplasm and nucleus (including nucleoli) in vivo and ex vivo, as determined by immunolabeling; GFP-fusion experiments confirm subcellular distribution. TMCO1 is expressed in trabecular meshwork and retina.","method":"Immunolabeling of human ocular tissues, GFP-fusion subcellular localization","journal":"Investigative ophthalmology & visual science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization by immunolabeling and GFP fusion, single lab, no functional consequence of nuclear localization established","pmids":["22714896"],"is_preprint":false},{"year":2025,"finding":"KALRN depletion suppresses TMCO1 expression in trabecular meshwork cells, and TMCO1 depletion phenocopies KALRN loss (ER dysfunction, Ca2+ dysregulation, energy metabolism impairment, cell senescence) and reduces KALRN expression, establishing KALRN and TMCO1 as interdependent regulators of ER and Ca2+ homeostasis. In vivo TMCO1 depletion elevated intraocular pressure in mice.","method":"siRNA knockdown in primary TM cells, mouse IOP measurements, Ca2+ homeostasis assays, energy metabolism assays, senescence assays, epistatic mutual suppression analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal epistasis between KALRN and TMCO1 with multiple orthogonal readouts and in vivo IOP validation; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.09.19.677310"],"is_preprint":true}],"current_model":"TMCO1 is an ER transmembrane protein that functions as a Ca2+ load-activated Ca2+ (CLAC) channel, forming homotetrамers in response to ER Ca2+ overload to release excess Ca2+ and prevent ER overfilling; its protein stability is regulated by Gp78-mediated ubiquitination at K186 (countered by iASPP), and its downstream Ca2+ signals control ERK/FGF pathway activity, lipid metabolism via DGAT2 stability, and mitochondrial function, with loss-of-function causing cerebrofaciothoracic dysplasia and gain-of-function linked to cancer and glaucoma phenotypes."},"narrative":{"mechanistic_narrative":"TMCO1 is an endoplasmic reticulum transmembrane protein that functions as a Ca2+ load-activated Ca2+ (CLAC) channel, reversibly homotetramerizing in response to ER Ca2+ overload to release excess Ca2+ and prevent ER overfilling, with loss of function causing supernormal ER Ca2+ signaling [PMID:27212239]. This Ca2+-handling role makes TMCO1 a guardian of ER homeostasis: its deficiency triggers excessive ER Ca2+ release, ER stress, ROS accumulation, and stress-mediated apoptosis in specialized cell types such as ovarian granulosa cells [PMID:29467381]. Downstream of its ER Ca2+ control, TMCO1 deficiency drives over-activation of ERK signaling through upregulated FGFs, and pharmacological MEK inhibition rescues the resulting corpus callosum defect, demonstrating that TMCO1-controlled Ca2+ signals feed into the ERK/FGF axis during development [PMID:35927240]. TMCO1-dependent ER stress also destabilizes the lipid enzyme DGAT2 via ERAD, linking the protein to triglyceride synthesis and mitochondrial oxidative function [PMID:30929916]. TMCO1 protein levels are themselves set by ER-associated degradation: the E3 ligase Gp78 ubiquitinates TMCO1 at K186 to drive its turnover, an activity competitively antagonized by the oncoprotein iASPP, which stabilizes TMCO1 and lowers ER Ca2+ stores [PMID:35121659]. Through these intersecting Ca2+, ERK, and metabolic outputs, TMCO1 has been implicated in cancer cell mitochondrial regulation and in trabecular meshwork dysfunction associated with elevated intraocular pressure [PMID:39343416, PMID:39566034].","teleology":[{"year":2016,"claim":"Established the core molecular identity of TMCO1: whether it had intrinsic channel activity was unknown until reconstitution showed it is an ER Ca2+ channel that gates by load-dependent oligomerization.","evidence":"Giant liposome electrophysiology, oligomer co-IP, and Tmco1 knockout mouse ER Ca2+ measurement","pmids":["27212239"],"confidence":"High","gaps":["No atomic structure of the mammalian tetramer or pore","Gating trigger sensing mechanism for Ca2+ overload not resolved at residue level"]},{"year":2018,"claim":"Tested the physiological consequence of TMCO1 channel loss in a defined tissue, showing it is required to restrain Ca2+ signaling and prevent ER-stress apoptosis in granulosa cells.","evidence":"Tmco1-/- mice with granulosa-cell Ca2+ imaging, ER stress and ROS assays, RNA-seq","pmids":["29467381"],"confidence":"High","gaps":["Does not establish whether the apoptotic phenotype is cell-type-specific or general","Link between Ca2+ overload and the specific death pathway not dissected"]},{"year":2019,"claim":"Connected TMCO1 ER stress to lipid and mitochondrial metabolism by identifying ERAD-mediated DGAT2 loss as the link to impaired triglyceride synthesis and OXPHOS.","evidence":"Tmco1-/- cells with lipid droplet/triglyceride quantification, DGAT2 protein analysis, mitochondrial function assays","pmids":["30929916"],"confidence":"Medium","gaps":["No reconstitution of the DGAT2-ER stress axis","Whether DGAT2 destabilization is direct or downstream of generalized ER stress unclear"]},{"year":2020,"claim":"Provided the first structural view of a TMCO1 ortholog, defining its three-transmembrane-helix architecture.","evidence":"Solution NMR of Dictyostelium TMCO1 in DPC micelles with recombinant protein purification","pmids":["33253810"],"confidence":"Medium","gaps":["Non-mammalian ortholog; relevance to human channel uncertain","No functional or mutagenesis validation of the structure"]},{"year":2022,"claim":"Resolved how TMCO1 abundance is controlled, identifying Gp78-mediated ubiquitination at K186 and its competitive inhibition by iASPP as a switch coupling protein stability to ER Ca2+ store size.","evidence":"Reciprocal co-IP, ubiquitination assays mapping K186, competitive binding, Ca2+ store measurement, tumor models","pmids":["35121659"],"confidence":"High","gaps":["Whether other E3 ligases also regulate TMCO1 not addressed","Physiological signals that tip the Gp78/iASPP balance unknown"]},{"year":2022,"claim":"Placed TMCO1 Ca2+ control upstream of a developmental signaling axis, showing its loss over-activates FGF/ERK to misroute midline glia, with MEK inhibition rescuing corpus callosum formation.","evidence":"Tmco1-/- mice, ERK phosphorylation and FGF/Slit2 expression analysis, MEK inhibitor rescue, brain histology","pmids":["35927240"],"confidence":"High","gaps":["Direct biochemical link between ER Ca2+ release and FGF upregulation not defined","Generality of the ERK axis to non-neural tissues untested"]},{"year":2024,"claim":"Extended TMCO1 function to cancer-associated mitochondrial and ECM phenotypes through ERK and TOMM20, framing TMCO1 as a context-dependent disease modifier.","evidence":"Trabecular meshwork ferroptosis/ECM model and hepatocellular carcinoma TOMM20 epistasis with multiple mitochondrial readouts and xenografts","pmids":["39343416","39566034"],"confidence":"Medium","gaps":["Direct physical interaction with TOMM20 not demonstrated","Whether these effects depend on TMCO1 channel activity unresolved"]},{"year":2024,"claim":"Probed TMCO1 protein interactions and subcellular distribution in cancer cells, reporting CALR/VDAC1 links, nuclear plus ER localization, and modulation of BCL-2/MCL-1 inhibitor sensitivity.","evidence":"Interactome MS, immunofluorescence, Ca2+ assays, and viability assays in ovarian and breast cancer lines","pmids":["38372107","39353922"],"confidence":"Low","gaps":["Single pulldown/Co-IP approaches without reciprocal validation of direct binding","Functional significance of reported nuclear localization not established","CALR interaction directness unconfirmed"]},{"year":2025,"claim":"Identified KALRN as an interdependent regulator of TMCO1 in trabecular meshwork ER/Ca2+ homeostasis, with TMCO1 depletion raising intraocular pressure.","evidence":"siRNA mutual-suppression epistasis in primary TM cells, Ca2+/energy/senescence assays, mouse IOP measurement (preprint)","pmids":["bio_10.1101_2025.09.19.677310"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Mechanism of reciprocal expression control between KALRN and TMCO1 unknown"]},{"year":null,"claim":"How the TMCO1 channel pore, oligomerization interface, and Ca2+ load-sensing are structurally implemented in the human protein, and how a single ER Ca2+ leak channel produces such diverse tissue-specific outputs, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of the human channel or gating residues","Unclear which downstream phenotypes require channel activity versus scaffolding","Disease-causing mutations not mechanistically mapped onto channel function in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,2,5]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[9,10]}],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4]}],"complexes":[],"partners":["GP78","IASPP","DGAT2","TOMM20","CALR","VDAC1","KALRN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UM00","full_name":"Calcium load-activated calcium channel","aliases":["GEL complex subunit TMCO1","Transmembrane and coiled-coil domain-containing protein 1","Transmembrane and coiled-coil domains protein 4","Xenogeneic cross-immune protein PCIA3"],"length_aa":239,"mass_kda":27.1,"function":"Endoplasmic reticulum (ER) calcium-selective channel preventing intracellular Ca2(+) stores from overfilling and maintaining calcium homeostasis in the ER (PubMed:27212239). In response to endoplasmic reticulum (ER) Ca2(+) overloading, assembles into a homotetramer, forming a functional calcium-selective channel facilitating Ca2(+) release (PubMed:27212239). Mediates ER Ca2(+) homeostasis in osteoblasts and plays a key role in bone formation, via the CaMKII-HDAC4-RUNX2 signaling axis (By similarity). Component of the multi-pass translocon (MPT) complex that mediates insertion of multi-pass membrane proteins into the lipid bilayer of membranes (PubMed:32820719, PubMed:36261522). The MPT complex takes over after the SEC61 complex: following membrane insertion of the first few transmembrane segments of proteins by the SEC61 complex, the MPT complex occludes the lateral gate of the SEC61 complex to promote insertion of subsequent transmembrane regions (PubMed:36261522). Within the MPT complex, the GEL subcomplex may mediate insertion of transmembrane regions into the membrane (PubMed:36261522)","subcellular_location":"Endoplasmic reticulum membrane; Golgi apparatus membrane; Mitochondrion membrane","url":"https://www.uniprot.org/uniprotkb/Q9UM00/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMCO1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":383,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000143183","cell_line_id":"CID001796","localizations":[{"compartment":"er","grade":3},{"compartment":"vesicles","grade":3},{"compartment":"golgi","grade":1}],"interactors":[{"gene":"C20ORF24","stoichiometry":10.0},{"gene":"EMC3","stoichiometry":4.0},{"gene":"PGRMC1","stoichiometry":4.0},{"gene":"RBM42","stoichiometry":4.0},{"gene":"CCDC47","stoichiometry":4.0},{"gene":"NCLN","stoichiometry":4.0},{"gene":"CANX","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"RAB14","stoichiometry":0.2},{"gene":"RBM8A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001796","total_profiled":1310},"omim":[{"mim_id":"619960","title":"RAB5-INTERACTING FACTOR; RAB5IF","url":"https://www.omim.org/entry/619960"},{"mim_id":"616994","title":"CRANIOFACIAL DYSMORPHISM, SKELETAL ANOMALIES, AND IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME 2; CFSMR2","url":"https://www.omim.org/entry/616994"},{"mim_id":"614123","title":"TRANSMEMBRANE AND COILED-COIL DOMAINS PROTEIN 1; TMCO1","url":"https://www.omim.org/entry/614123"},{"mim_id":"613149","title":"CDKN2B ANTISENSE RNA; CDKN2BAS","url":"https://www.omim.org/entry/613149"},{"mim_id":"600431","title":"CYCLIN-DEPENDENT KINASE INHIBITOR 2B; CDKN2B","url":"https://www.omim.org/entry/600431"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TMCO1"},"hgnc":{"alias_symbol":["HP10122"],"prev_symbol":["TMCC4"]},"alphafold":{"accession":"Q9UM00","domains":[{"cath_id":"-","chopping":"53-217","consensus_level":"medium","plddt":72.9581,"start":53,"end":217}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UM00","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UM00-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UM00-F1-predicted_aligned_error_v6.png","plddt_mean":63.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMCO1","jax_strain_url":"https://www.jax.org/strain/search?query=TMCO1"},"sequence":{"accession":"Q9UM00","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UM00.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UM00/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UM00"}},"corpus_meta":[{"pmid":"21532571","id":"PMC_21532571","title":"Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1.","date":"2011","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21532571","citation_count":352,"is_preprint":false},{"pmid":"27212239","id":"PMC_27212239","title":"TMCO1 Is an ER Ca(2+) Load-Activated Ca(2+) Channel.","date":"2016","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/27212239","citation_count":129,"is_preprint":false},{"pmid":"29467381","id":"PMC_29467381","title":"TMCO1 is essential for ovarian follicle development by regulating ER Ca2+ store of granulosa cells.","date":"2018","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/29467381","citation_count":74,"is_preprint":false},{"pmid":"20018682","id":"PMC_20018682","title":"Homozygous frameshift mutation in TMCO1 causes a syndrome with craniofacial dysmorphism, skeletal anomalies, and mental retardation.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20018682","citation_count":58,"is_preprint":false},{"pmid":"22714896","id":"PMC_22714896","title":"Association of genetic variants in the TMCO1 gene with clinical parameters related to glaucoma and characterization of the protein in the eye.","date":"2012","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/22714896","citation_count":40,"is_preprint":false},{"pmid":"24194475","id":"PMC_24194475","title":"TMCO1 deficiency causes autosomal recessive cerebrofaciothoracic dysplasia.","date":"2013","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/24194475","citation_count":31,"is_preprint":false},{"pmid":"35121659","id":"PMC_35121659","title":"iASPP suppresses Gp78-mediated TMCO1 degradation to maintain Ca2+ homeostasis and control tumor growth and drug resistance.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/35121659","citation_count":30,"is_preprint":false},{"pmid":"19449125","id":"PMC_19449125","title":"Molecular cloning, expression patterns and subcellular localization of porcine TMCO1 gene.","date":"2009","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/19449125","citation_count":26,"is_preprint":false},{"pmid":"24424126","id":"PMC_24424126","title":"Whole-exome sequencing links TMCO1 defect syndrome with cerebro-facio-thoracic dysplasia.","date":"2014","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/24424126","citation_count":19,"is_preprint":false},{"pmid":"30929916","id":"PMC_30929916","title":"ER stress mediated degradation of diacylglycerol acyltransferase impairs mitochondrial functions in TMCO1 deficient cells.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/30929916","citation_count":17,"is_preprint":false},{"pmid":"35568751","id":"PMC_35568751","title":"TMCO1 expression promotes cell proliferation and induces epithelial-mesenchymal transformation in human gliomas.","date":"2022","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/35568751","citation_count":11,"is_preprint":false},{"pmid":"30556256","id":"PMC_30556256","title":"Cerebrofaciothoracic dysplasia: Four new patients with a recurrent TMCO1 pathogenic variant.","date":"2018","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/30556256","citation_count":11,"is_preprint":false},{"pmid":"30862618","id":"PMC_30862618","title":"SNP located in an AluJb repeat downstream of TMCO1, rs4657473, is protective for POAG in African Americans.","date":"2019","source":"The British journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/30862618","citation_count":10,"is_preprint":false},{"pmid":"27687253","id":"PMC_27687253","title":"Polymorphism rs7555523 in transmembrane and coiled-coil domain 1 (TMCO1) is not a risk factor for primary open angle glaucoma in a Saudi cohort.","date":"2016","source":"Journal of negative results in biomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/27687253","citation_count":10,"is_preprint":false},{"pmid":"35927240","id":"PMC_35927240","title":"Ca2+ homeostasis maintained by TMCO1 underlies corpus callosum development via ERK signaling.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/35927240","citation_count":9,"is_preprint":false},{"pmid":"31102500","id":"PMC_31102500","title":"A novel biallelic loss-of-function mutation in TMCO1 gene confirming and expanding the phenotype spectrum of cerebro-facio-thoracic dysplasia.","date":"2019","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/31102500","citation_count":9,"is_preprint":false},{"pmid":"34093650","id":"PMC_34093650","title":"From Disease Description and Gene Discovery to Functional Cell Pathway: A Decade-Long Journey for TMCO1.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34093650","citation_count":7,"is_preprint":false},{"pmid":"39343416","id":"PMC_39343416","title":"TMCO1 promotes ferroptosis and ECM deposition in glaucomatous trabecular meshwork via ERK1/2 signaling.","date":"2024","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/39343416","citation_count":6,"is_preprint":false},{"pmid":"36186440","id":"PMC_36186440","title":"Uniparental disomy screen of Irish rare disorder cohort unmasks homozygous variants of clinical significance in the TMCO1 and PRKRA genes.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36186440","citation_count":6,"is_preprint":false},{"pmid":"36708876","id":"PMC_36708876","title":"Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome-1 in two new patients with the same homozygous TMCO1 variant and review of the literature.","date":"2023","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36708876","citation_count":4,"is_preprint":false},{"pmid":"38372107","id":"PMC_38372107","title":"TMCO1 regulates cell proliferation, metastasis and EMT signaling through CALR, promoting ovarian cancer progression and cisplatin resistance.","date":"2024","source":"Cellular and molecular biology (Noisy-le-Grand, France)","url":"https://pubmed.ncbi.nlm.nih.gov/38372107","citation_count":4,"is_preprint":false},{"pmid":"39353922","id":"PMC_39353922","title":"TMCO1 is upregulated in breast cancer and regulates the response to pro-apoptotic agents in breast cancer cells.","date":"2024","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/39353922","citation_count":4,"is_preprint":false},{"pmid":"33253810","id":"PMC_33253810","title":"Expression, purification and characterization of TMCO1 for structural studies.","date":"2020","source":"Protein expression and purification","url":"https://pubmed.ncbi.nlm.nih.gov/33253810","citation_count":2,"is_preprint":false},{"pmid":"39479348","id":"PMC_39479348","title":"The relationship between TMCO1 and CALR in the pathological characteristics of prostate cancer and its effect on the metastasis of prostate cancer cells.","date":"2024","source":"Open life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39479348","citation_count":2,"is_preprint":false},{"pmid":"36451910","id":"PMC_36451910","title":"Brain and spine MRI findings in children presenting with TMCO1 mutation.","date":"2022","source":"BJR case reports","url":"https://pubmed.ncbi.nlm.nih.gov/36451910","citation_count":1,"is_preprint":false},{"pmid":"39566034","id":"PMC_39566034","title":"TMCO1 regulates energy metabolism and mitochondrial function of hepatocellular carcinoma cells through TOMM20, affecting the growth of subcutaneous graft tumors and infiltration of CAFs.","date":"2024","source":"Biochemistry and cell biology = Biochimie et biologie cellulaire","url":"https://pubmed.ncbi.nlm.nih.gov/39566034","citation_count":1,"is_preprint":false},{"pmid":"40867644","id":"PMC_40867644","title":"TMCO1 as an Endoplasmic Reticulum Calcium Load-Activated Channel: Mechanisms and Disease Implications.","date":"2025","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/40867644","citation_count":0,"is_preprint":false},{"pmid":"39725295","id":"PMC_39725295","title":"Tmco1-Deficient Mice Exhibit a High Incidence of Otitis Media Associated with Impaired Bone Homeostasis in the Middle Ear.","date":"2024","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/39725295","citation_count":0,"is_preprint":false},{"pmid":"41049620","id":"PMC_41049620","title":"Anomalous Origin of the Left Anterior Descending Artery From the Pulmonary Artery in an Infant With TMCO1 Mutation and Cohen Syndrome.","date":"2025","source":"CASE (Philadelphia, Pa.)","url":"https://pubmed.ncbi.nlm.nih.gov/41049620","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.19.677310","title":"Interdependent regulation of trabecular meshwork cell physiology and intraocular pressure by KALRN and TMCO1","date":"2025-09-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.19.677310","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15815,"output_tokens":3225,"usd":0.04791,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10743,"output_tokens":3396,"usd":0.069307,"stage2_stop_reason":"end_turn"},"total_usd":0.117217,"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\": \"TMCO1 is an ER transmembrane protein that forms a Ca2+-selective ion channel ('Ca2+ load-activated Ca2+ channel', CLAC) on giant liposomes and undergoes reversible homotetramerization in response to ER Ca2+ overloading, dissociating upon Ca2+ depletion, thereby preventing ER Ca2+ overfilling.\",\n      \"method\": \"Giant liposome electrophysiology, co-immunoprecipitation of oligomeric complexes, TMCO1 knockout mouse model with ER Ca2+ measurement, in vitro reconstitution\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted ion channel activity in giant liposomes, biochemical characterization of homotetramerization, KO mouse phenotype, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"27212239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TMCO1 protein from Dictyostelium discoideum (ortholog) contains three α-helical transmembrane regions as determined by solution NMR in DPC micelles; recombinant protein was successfully purified by affinity and size exclusion chromatography.\",\n      \"method\": \"Solution NMR spectroscopy in DPC micelles, recombinant protein expression and purification (E. coli and insect cells)\",\n      \"journal\": \"Protein expression and purification\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — NMR structural characterization in a non-mammalian ortholog, single lab, no mutagenesis or functional validation reported in abstract\",\n      \"pmids\": [\"33253810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TMCO1 is essential for ovarian follicle development; its ablation in granulosa cells causes supernormal Ca2+ signaling, ER stress-mediated apoptosis, and elevated ROS, while ER Ca2+ stores in oocytes remain normal, placing TMCO1 specifically in granulosa cell Ca2+ homeostasis.\",\n      \"method\": \"Tmco1-/- knockout mice, Ca2+ imaging in granulosa cells, RNA-sequencing, ER stress and ROS assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with specific cellular Ca2+ phenotype, multiple orthogonal readouts (Ca2+ imaging, ROS, ER stress markers, RNA-seq), single lab\",\n      \"pmids\": [\"29467381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TMCO1 is a substrate of the ER-associated degradation E3 ubiquitin ligase Gp78, which ubiquitinates TMCO1 at K186 to promote its degradation. The oncoprotein iASPP competitively binds Gp78, interfering with Gp78-mediated TMCO1 ubiquitination and thus stabilizing TMCO1 protein levels and reducing ER Ca2+ stores.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, competitive binding assay, Ca2+ store measurements, in vitro and in vivo tumor models\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP identifying specific ubiquitination site (K186), competitive binding mechanism, functional Ca2+ readout, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"35121659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TMCO1 is required for normal corpus callosum development; TMCO1 deficiency causes excessive ER Ca2+ release leading to upregulation of FGFs, over-activation of ERK signaling, excess midline glial cell migration, and overproduction of Slit2, which repels neural fiber bundles from crossing the midline. Pharmacological MEK inhibition rescues corpus callosum formation in Tmco1-/- mice.\",\n      \"method\": \"Tmco1-/- knockout mice, ERK phosphorylation assays, FGF/Slit2 expression analysis, MEK inhibitor rescue experiments, brain histology\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined cellular phenotype, mechanistic pathway delineation via epistasis (MEK inhibitor rescue), multiple molecular readouts (ERK, FGFs, Slit2), single lab\",\n      \"pmids\": [\"35927240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In TMCO1-deficient cells, ER stress causes ERAD-mediated degradation of diacylglycerol acyltransferase 2 (DGAT2), reducing triglyceride synthesis, causing non-esterified fatty acid accumulation, and resulting in decreased mitochondrial volume, enhanced mitophagy, and impaired oxidative phosphorylation.\",\n      \"method\": \"Tmco1-/- cells, lipid droplet quantification, triglyceride measurement, DGAT2 protein level analysis, mitochondrial morphology and function assays (OXPHOS)\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO cells with specific molecular pathway (ERAD of DGAT2), multiple metabolic readouts, single lab, no direct reconstitution\",\n      \"pmids\": [\"30929916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TMCO1 promotes ferroptosis and ECM deposition in trabecular meshwork cells through ERK1/2 signaling; dexamethasone stimulation upregulates TMCO1, and ferroptosis inhibitor ferrostatin-1 reduces both ECM deposition and ferroptosis downstream of TMCO1.\",\n      \"method\": \"In vivo glaucoma model, HTM cell culture, dexamethasone stimulation, ferrostatin-1 treatment, ERK1/2 phosphorylation assays, ECM marker quantification\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo and in vitro models with pathway placement (ERK/MAPK), but single lab and abstract-level detail limits mechanistic granularity\",\n      \"pmids\": [\"39343416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TMCO1 regulates mitochondrial function in hepatocellular carcinoma cells via TOMM20; TMCO1 overexpression promotes ATP production, increases mitochondrial membrane potential, and inhibits mPTP opening and ROS, while TOMM20 knockdown blocks these TMCO1-mediated effects, placing TOMM20 epistatically downstream of TMCO1.\",\n      \"method\": \"TMCO1 overexpression and knockdown, TOMM20 knockdown epistasis, ROS assay, mPTP assay, MMP assay, ATP measurement, subcutaneous xenograft mouse model\",\n      \"journal\": \"Biochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — epistatic genetic rescue (TOMM20 KD blocks TMCO1 effects), multiple mitochondrial readouts, single lab\",\n      \"pmids\": [\"39566034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TMCO1 interacts with CALR (calreticulin) in ovarian cancer cells; TMCO1 overexpression upregulates CALR and VDAC1 and elevates intracellular Ca2+, while TMCO1 knockout reduces CALR and VDAC1 expression and reverses the pro-metastatic effects of CALR recombinant protein.\",\n      \"method\": \"TMCO1 overexpression and knockout, CALR/VDAC1 knockdown epistasis, Fluo-4 Ca2+ assay, ER/mitochondrial fluorescent probes, Transwell assay, Western blot, xenograft mouse model\",\n      \"journal\": \"Cellular and molecular biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/epistasis approach inferred from abstract, functional readouts present but limited mechanistic resolution on direct binding\",\n      \"pmids\": [\"38372107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In breast cancer cells, TMCO1 interacting proteins include ER-resident Ca2+-regulatory proteins and nuclear transport proteins; TMCO1 localizes to both the nucleus and ER in MDA-MB-231 cells, and TMCO1 regulates sensitivity to BCL-2/MCL-1 inhibitors analogously to IP3 receptors.\",\n      \"method\": \"Interactome pulldown/MS for TMCO1 binding partners, immunofluorescence for localization, cell viability assays with BCL-2/MCL-1 inhibitors\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single pulldown/MS for interactors, localization by immunofluorescence without deep functional validation, single lab\",\n      \"pmids\": [\"39353922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In human ocular tissues, endogenous TMCO1 protein localizes to the cytoplasm and nucleus (including nucleoli) in vivo and ex vivo, as determined by immunolabeling; GFP-fusion experiments confirm subcellular distribution. TMCO1 is expressed in trabecular meshwork and retina.\",\n      \"method\": \"Immunolabeling of human ocular tissues, GFP-fusion subcellular localization\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization by immunolabeling and GFP fusion, single lab, no functional consequence of nuclear localization established\",\n      \"pmids\": [\"22714896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KALRN depletion suppresses TMCO1 expression in trabecular meshwork cells, and TMCO1 depletion phenocopies KALRN loss (ER dysfunction, Ca2+ dysregulation, energy metabolism impairment, cell senescence) and reduces KALRN expression, establishing KALRN and TMCO1 as interdependent regulators of ER and Ca2+ homeostasis. In vivo TMCO1 depletion elevated intraocular pressure in mice.\",\n      \"method\": \"siRNA knockdown in primary TM cells, mouse IOP measurements, Ca2+ homeostasis assays, energy metabolism assays, senescence assays, epistatic mutual suppression analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal epistasis between KALRN and TMCO1 with multiple orthogonal readouts and in vivo IOP validation; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.09.19.677310\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"TMCO1 is an ER transmembrane protein that functions as a Ca2+ load-activated Ca2+ (CLAC) channel, forming homotetrамers in response to ER Ca2+ overload to release excess Ca2+ and prevent ER overfilling; its protein stability is regulated by Gp78-mediated ubiquitination at K186 (countered by iASPP), and its downstream Ca2+ signals control ERK/FGF pathway activity, lipid metabolism via DGAT2 stability, and mitochondrial function, with loss-of-function causing cerebrofaciothoracic dysplasia and gain-of-function linked to cancer and glaucoma phenotypes.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TMCO1 is an endoplasmic reticulum transmembrane protein that functions as a Ca2+ load-activated Ca2+ (CLAC) channel, reversibly homotetramerizing in response to ER Ca2+ overload to release excess Ca2+ and prevent ER overfilling, with loss of function causing supernormal ER Ca2+ signaling [#0]. This Ca2+-handling role makes TMCO1 a guardian of ER homeostasis: its deficiency triggers excessive ER Ca2+ release, ER stress, ROS accumulation, and stress-mediated apoptosis in specialized cell types such as ovarian granulosa cells [#2]. Downstream of its ER Ca2+ control, TMCO1 deficiency drives over-activation of ERK signaling through upregulated FGFs, and pharmacological MEK inhibition rescues the resulting corpus callosum defect, demonstrating that TMCO1-controlled Ca2+ signals feed into the ERK/FGF axis during development [#4]. TMCO1-dependent ER stress also destabilizes the lipid enzyme DGAT2 via ERAD, linking the protein to triglyceride synthesis and mitochondrial oxidative function [#5]. TMCO1 protein levels are themselves set by ER-associated degradation: the E3 ligase Gp78 ubiquitinates TMCO1 at K186 to drive its turnover, an activity competitively antagonized by the oncoprotein iASPP, which stabilizes TMCO1 and lowers ER Ca2+ stores [#3]. Through these intersecting Ca2+, ERK, and metabolic outputs, TMCO1 has been implicated in cancer cell mitochondrial regulation and in trabecular meshwork dysfunction associated with elevated intraocular pressure [#6, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established the core molecular identity of TMCO1: whether it had intrinsic channel activity was unknown until reconstitution showed it is an ER Ca2+ channel that gates by load-dependent oligomerization.\",\n      \"evidence\": \"Giant liposome electrophysiology, oligomer co-IP, and Tmco1 knockout mouse ER Ca2+ measurement\",\n      \"pmids\": [\"27212239\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No atomic structure of the mammalian tetramer or pore\", \"Gating trigger sensing mechanism for Ca2+ overload not resolved at residue level\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Tested the physiological consequence of TMCO1 channel loss in a defined tissue, showing it is required to restrain Ca2+ signaling and prevent ER-stress apoptosis in granulosa cells.\",\n      \"evidence\": \"Tmco1-/- mice with granulosa-cell Ca2+ imaging, ER stress and ROS assays, RNA-seq\",\n      \"pmids\": [\"29467381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish whether the apoptotic phenotype is cell-type-specific or general\", \"Link between Ca2+ overload and the specific death pathway not dissected\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected TMCO1 ER stress to lipid and mitochondrial metabolism by identifying ERAD-mediated DGAT2 loss as the link to impaired triglyceride synthesis and OXPHOS.\",\n      \"evidence\": \"Tmco1-/- cells with lipid droplet/triglyceride quantification, DGAT2 protein analysis, mitochondrial function assays\",\n      \"pmids\": [\"30929916\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconstitution of the DGAT2-ER stress axis\", \"Whether DGAT2 destabilization is direct or downstream of generalized ER stress unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided the first structural view of a TMCO1 ortholog, defining its three-transmembrane-helix architecture.\",\n      \"evidence\": \"Solution NMR of Dictyostelium TMCO1 in DPC micelles with recombinant protein purification\",\n      \"pmids\": [\"33253810\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Non-mammalian ortholog; relevance to human channel uncertain\", \"No functional or mutagenesis validation of the structure\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved how TMCO1 abundance is controlled, identifying Gp78-mediated ubiquitination at K186 and its competitive inhibition by iASPP as a switch coupling protein stability to ER Ca2+ store size.\",\n      \"evidence\": \"Reciprocal co-IP, ubiquitination assays mapping K186, competitive binding, Ca2+ store measurement, tumor models\",\n      \"pmids\": [\"35121659\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other E3 ligases also regulate TMCO1 not addressed\", \"Physiological signals that tip the Gp78/iASPP balance unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed TMCO1 Ca2+ control upstream of a developmental signaling axis, showing its loss over-activates FGF/ERK to misroute midline glia, with MEK inhibition rescuing corpus callosum formation.\",\n      \"evidence\": \"Tmco1-/- mice, ERK phosphorylation and FGF/Slit2 expression analysis, MEK inhibitor rescue, brain histology\",\n      \"pmids\": [\"35927240\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical link between ER Ca2+ release and FGF upregulation not defined\", \"Generality of the ERK axis to non-neural tissues untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended TMCO1 function to cancer-associated mitochondrial and ECM phenotypes through ERK and TOMM20, framing TMCO1 as a context-dependent disease modifier.\",\n      \"evidence\": \"Trabecular meshwork ferroptosis/ECM model and hepatocellular carcinoma TOMM20 epistasis with multiple mitochondrial readouts and xenografts\",\n      \"pmids\": [\"39343416\", \"39566034\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interaction with TOMM20 not demonstrated\", \"Whether these effects depend on TMCO1 channel activity unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Probed TMCO1 protein interactions and subcellular distribution in cancer cells, reporting CALR/VDAC1 links, nuclear plus ER localization, and modulation of BCL-2/MCL-1 inhibitor sensitivity.\",\n      \"evidence\": \"Interactome MS, immunofluorescence, Ca2+ assays, and viability assays in ovarian and breast cancer lines\",\n      \"pmids\": [\"38372107\", \"39353922\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single pulldown/Co-IP approaches without reciprocal validation of direct binding\", \"Functional significance of reported nuclear localization not established\", \"CALR interaction directness unconfirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified KALRN as an interdependent regulator of TMCO1 in trabecular meshwork ER/Ca2+ homeostasis, with TMCO1 depletion raising intraocular pressure.\",\n      \"evidence\": \"siRNA mutual-suppression epistasis in primary TM cells, Ca2+/energy/senescence assays, mouse IOP measurement (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.09.19.677310\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Mechanism of reciprocal expression control between KALRN and TMCO1 unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the TMCO1 channel pore, oligomerization interface, and Ca2+ load-sensing are structurally implemented in the human protein, and how a single ER Ca2+ leak channel produces such diverse tissue-specific outputs, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of the human channel or gating residues\", \"Unclear which downstream phenotypes require channel activity versus scaffolding\", \"Disease-causing mutations not mechanistically mapped onto channel function in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005262\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"Gp78\",\n      \"iASPP\",\n      \"DGAT2\",\n      \"TOMM20\",\n      \"CALR\",\n      \"VDAC1\",\n      \"KALRN\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}