{"gene":"FLVCR2","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2010,"finding":"FLVCR2 functions as an importer of heme: it binds hemin-conjugated agarose (competed by free hemin), and mammalian cells and Xenopus oocytes expressing FLVCR2 display enhanced heme uptake. siRNA knockdown of FLVCR2 or binding of FY981 FeLV envelope protein to FLVCR2 reduces heme import. Cells overexpressing FLVCR2 show increased sensitivity to heme toxicity consistent with enhanced uptake.","method":"Hemin-agarose pulldown, heterologous expression in Xenopus oocytes and mammalian cells with radiolabeled heme uptake assays, siRNA knockdown, retroviral envelope competition","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (binding assay, functional uptake in two heterologous systems, siRNA, competitive inhibition) in a single rigorous study establishing transporter function","pmids":["20823265"],"is_preprint":false},{"year":2009,"finding":"FLVCR2 functions as a cell-surface receptor for the FY981 feline leukemia virus (FeLV), enabling viral infection of porcine ST-IOWA cells that are resistant to both FeLV-A and FeLV-C; FLVCR2 is distinct from but related to FLVCR1.","method":"Pseudotype virus infection assays across multiple cell lines; receptor identification by functional complementation and competition","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional infection assays in multiple cell types in one study, but receptor identity inferred primarily from infection phenotype without direct binding reconstitution","pmids":["19369334"],"is_preprint":false},{"year":2010,"finding":"Loss-of-function mutations in FLVCR2 cause Fowler syndrome (proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome), an autosomal recessive prenatal lethal disorder; five distinct germline mutations identified by autozygosity mapping and direct sequencing in five families, establishing FLVCR2 as the causative gene.","method":"Autozygosity mapping (SNP microarray), microsatellite genotyping, direct sequencing of candidate genes in consanguineous families","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Strong — genetic mapping with multiple independent families establishes disease causation, but mechanism is inferred rather than directly reconstituted","pmids":["20206334"],"is_preprint":false},{"year":2010,"finding":"FLVCR2 mutations (including a large deletion) were identified in lethal cerebral vasculopathy (Fowler syndrome/PGV); absence of alpha-smooth muscle actin immunostaining in abnormal fetal PGV brain vessels suggests a deficit in pericytes essential for capillary stabilization during brain angiogenesis.","method":"High-throughput sequencing of a 4.1 Mb linkage interval after sequence capture; immunostaining of fetal brain tissue","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — HTS-based gene identification in multiple families plus histological phenotyping; pericyte deficit is an observed correlate, not experimentally manipulated","pmids":["20690116"],"is_preprint":false},{"year":2020,"finding":"MFSD7C (FLVCR2) uncouples mitochondrial respiration to switch ATP synthesis to thermogenesis in response to heme. When heme levels are low, MFSD7C promotes ATP synthesis by interacting with components of electron transport chain (ETC) complexes III, IV, and V and destabilizing SERCA2b. Upon heme binding to the N-terminal domain, MFSD7C dissociates from ETC components and SERCA2b, resulting in SERCA2b stabilization and thermogenesis.","method":"Co-immunoprecipitation with ETC components, heme-binding assays to N-terminal domain, functional measurement of ATP synthesis vs. thermogenesis, SERCA2b stability assays, loss-of-function studies","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP with ETC components, domain-level heme binding, functional metabolic readouts (ATP vs. heat), and mechanistic dissection of heme-regulated conformational switch in one rigorous study","pmids":["32973183"],"is_preprint":false},{"year":2020,"finding":"Flvcr2 (Mfsd7c) is required for angiogenic sprouting in the brain but is dispensable for blood-brain barrier maintenance. Endothelial cells lacking Flvcr2 fail to adopt tip cell properties, show altered expression of angiogenic factors, and display reduced sprouting, leading to glomeruloid vascular malformations, brain hypovascularization, hypoxia, and hydrocephalus in mice.","method":"Conditional and global Flvcr2 knockout mice; analysis of vascular morphology, tip cell markers, angiogenic factor expression, BBB integrity assays, histology","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with multiple defined cellular phenotypes (tip cell failure, sprouting defect, BBB integrity uncoupling) establishing pathway position in brain angiogenesis","pmids":["32369453"],"is_preprint":false},{"year":2020,"finding":"Global knockout of Mfsd7c (FLVCR2) in mice results in late-gestation lethality with inhibited angiogenic growth of CNS blood vessels, dilated and fused vascular tips forming glomeruloid vessels, reduced cerebral cortical layers, enlarged ventricles, and microcephaly; transcriptomic analysis revealed upregulation of genes in glycolysis and angiogenesis pathways, and brain hypoxia with neuronal cell death.","method":"Global Mfsd7c knockout mice; histology, transcriptomics, hypoxia marker staining, comparison with human FLVCR2 mutation phenotypes","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple orthogonal phenotypic and molecular readouts; independently replicates vascular phenotype seen in human Fowler syndrome","pmids":["32369449"],"is_preprint":false},{"year":2024,"finding":"FLVCR2 is a blood-brain barrier choline transporter responsible for the majority of choline uptake into the brain. Cryo-EM structures of choline-bound FLVCR2 in both inward-facing and outward-facing states reveal that choline binds within an aromatic cage. In vivo and in vitro experiments confirm FLVCR2-mediated choline import at the BBB.","method":"Cryo-EM structure determination (inward- and outward-facing states), in vivo choline uptake studies in mice, in vitro transport assays, aromatic cage identification by structural analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — near-atomic cryo-EM structures in two conformational states plus in vivo and in vitro functional validation; establishes molecular mechanism of choline binding and transport","pmids":["38693257"],"is_preprint":false},{"year":2024,"finding":"MFSD7c (FLVCR2) functions as a facilitative choline transporter at the blood-brain barrier; choline uptake is electrogenic (shown by patch clamp), greatly enhanced by choline-metabolizing enzymes, and conserved in vertebrates but not yeast. MFSD7c is a functional ortholog of the yeast choline importer HNM1. Missense mutations from Fowler syndrome patients abolish or reduce choline transport activity. Endothelial-specific KO suppresses exogenous choline import from blood but paradoxically increases brain choline levels via impaired export of choline derived from lysophosphatidylcholine.","method":"Cell-based choline uptake assays, metabolomics of Mfsd7c-/- embryo brains and livers, single-cell patch clamp electrophysiology, stable-isotope tracing, endothelial-specific KO mice, functional complementation of yeast HNM1 mutant, patient mutation functional analysis","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (electrophysiology, isotope tracing, metabolomics, genetic KO, heterologous complementation, patient mutation testing) establishing transport mechanism and direction","pmids":["38302740"],"is_preprint":false}],"current_model":"FLVCR2 (MFSD7C/SLC49A2) is a 12-transmembrane major facilitator superfamily transporter expressed at the blood-brain barrier endothelium that primarily mediates choline transport into (and export of lysophosphatidylcholine-derived choline out of) the brain via an aromatic-cage binding site, as revealed by cryo-EM structures in inward- and outward-facing states; it also binds heme and, in response to heme, uncouples mitochondrial respiration from ATP synthesis to thermogenesis by dissociating from ETC complexes III/IV/V and stabilizing SERCA2b; loss-of-function mutations cause Fowler syndrome through failure of brain endothelial tip-cell-mediated angiogenic sprouting, leading to glomeruloid vasculopathy, hydrocephalus, and prenatal lethality."},"narrative":{"mechanistic_narrative":"FLVCR2 (MFSD7C/SLC49A2) is a multi-pass major facilitator superfamily transporter that governs choline supply to the brain and is essential for cerebral angiogenesis [PMID:38693257, PMID:32369453]. It is the principal blood-brain barrier choline importer: cryo-EM structures captured in inward- and outward-facing states show choline bound within an aromatic cage, and in vivo and in vitro assays confirm FLVCR2-mediated choline uptake [PMID:38693257]. Transport is facilitative and electrogenic, enhanced by downstream choline-metabolizing enzymes, and functionally conserved to the extent that FLVCR2 complements the yeast choline importer HNM1; beyond import from blood, it also mediates export of lysophosphatidylcholine-derived choline, such that endothelial loss paradoxically raises brain choline [PMID:38302740]. The same transporter binds heme and was independently characterized as a heme importer whose overexpression sensitizes cells to heme toxicity [PMID:20823265], and at the mitochondrion heme binding to its N-terminal domain triggers dissociation from electron transport chain complexes III/IV/V and stabilization of SERCA2b, switching respiration from ATP synthesis toward thermogenesis [PMID:32973183]. FLVCR2 is required for endothelial tip-cell formation and angiogenic sprouting in the CNS but dispensable for blood-brain barrier maintenance; its loss produces glomeruloid vascular malformations, brain hypovascularization, hypoxia, and hydrocephalus [PMID:32369453, PMID:32369449]. Loss-of-function mutations in FLVCR2 cause autosomal recessive, prenatally lethal Fowler syndrome (proliferative vasculopathy with hydranencephaly-hydrocephaly), and patient missense mutations abolish or reduce choline transport activity [PMID:20206334, PMID:38302740]. FLVCR2 also serves as a cell-surface entry receptor for FY981 feline leukemia virus [PMID:19369334].","teleology":[{"year":2009,"claim":"Identification of FLVCR2 as a functional receptor answered what cell-surface molecule mediates FY981 FeLV entry, distinguishing it from the related FLVCR1.","evidence":"Pseudotype virus infection and functional complementation across resistant and permissive cell lines","pmids":["19369334"],"confidence":"Medium","gaps":["Receptor role inferred from infection phenotype without direct virus-protein binding reconstitution","Relationship between viral receptor function and physiological transport activity not addressed"]},{"year":2010,"claim":"Demonstrating heme binding and heme uptake established a biochemical transport activity for FLVCR2, framing it as a heme importer.","evidence":"Hemin-agarose pulldown with free-hemin competition, radiolabeled heme uptake in Xenopus oocytes and mammalian cells, siRNA knockdown, and FeLV envelope competition","pmids":["20823265"],"confidence":"High","gaps":["Did not establish the physiological substrate in vivo","Direction and tissue context of heme transport not resolved","Relationship of heme handling to later-identified choline transport unclear"]},{"year":2010,"claim":"Genetic mapping in consanguineous families answered whether FLVCR2 is a disease gene, establishing it as the cause of Fowler syndrome and linking it to brain vascular development.","evidence":"Autozygosity mapping, targeted/high-throughput sequencing, and fetal brain immunostaining across multiple families","pmids":["20206334","20690116"],"confidence":"Medium","gaps":["Disease mechanism inferred genetically rather than reconstituted","Pericyte/smooth-muscle-actin deficit was an observed correlate, not experimentally manipulated","How loss of transport activity produces vasculopathy unaddressed"]},{"year":2020,"claim":"Conditional and global knockout mice answered where FLVCR2 acts in the vasculature, showing it is required for endothelial tip-cell formation and CNS angiogenic sprouting but not for blood-brain barrier maintenance, and that loss recapitulates the human glomeruloid vasculopathy.","evidence":"Conditional and global Flvcr2/Mfsd7c knockout mice with vascular morphology, tip-cell markers, transcriptomics, hypoxia staining, and BBB integrity assays","pmids":["32369453","32369449"],"confidence":"High","gaps":["Molecular substrate driving the angiogenic phenotype not defined","Mechanism linking transporter activity to tip-cell gene expression unknown"]},{"year":2020,"claim":"Mechanistic dissection at the mitochondrion answered how heme regulates FLVCR2, revealing a heme-triggered conformational switch that uncouples respiration toward thermogenesis.","evidence":"Reciprocal co-immunoprecipitation with ETC complexes III/IV/V, N-terminal-domain heme-binding assays, SERCA2b stability assays, and ATP-versus-heat functional readouts","pmids":["32973183"],"confidence":"High","gaps":["How mitochondrial thermogenic role integrates with plasma-membrane transport function not reconciled","Physiological relevance to brain vascular phenotype not established"]},{"year":2024,"claim":"Cryo-EM structures and functional validation answered the molecular identity of FLVCR2's principal physiological substrate, defining it as the blood-brain barrier choline transporter and resolving the choline-binding aromatic cage in two conformational states.","evidence":"Cryo-EM in inward- and outward-facing states, in vivo mouse choline uptake, in vitro transport assays, patch-clamp electrophysiology, stable-isotope tracing, metabolomics, endothelial-specific KO, yeast HNM1 complementation, and patient-mutation testing","pmids":["38693257","38302740"],"confidence":"High","gaps":["How choline transport mechanistically drives angiogenic sprouting not resolved","Relationship between choline transport and the separately reported heme functions unintegrated","Energetic coupling of the facilitative/electrogenic cycle only partly defined"]},{"year":null,"claim":"It remains unknown how FLVCR2's choline transport, heme handling, and mitochondrial thermogenic activities are mechanistically reconciled within one protein, and how transport activity is causally linked to endothelial tip-cell behavior and Fowler syndrome pathology.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model connecting substrate transport to the angiogenic and disease phenotypes","Subcellular partitioning between plasma membrane and mitochondrion not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,7,8]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,4]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7,8]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[7,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,6]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3]}],"complexes":[],"partners":["SERCA2B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UPI3","full_name":"Choline/ethanolamine transporter FLVCR2","aliases":["Calcium-chelate transporter","CCT","Feline leukemia virus subgroup C receptor-related protein 2","Heme transporter FLVCR2"],"length_aa":526,"mass_kda":57.2,"function":"Choline uniporter that specifically mediates choline uptake at the blood-brain-barrier (PubMed:38302740, PubMed:38778100). Responsible for the majority of choline uptake across the blood-brain-barrier from the circulation into the brain (By similarity). Choline, a nutrient critical for brain development, is a precursor of phosphatidylcholine, as well as betaine (By similarity). Also mediates transport of ethanolamine (PubMed:38778100). Choline and ethanolamine transport is not coupled with proton transport and is exclusively driven by the choline gradient across the plasma membrane (PubMed:38778100). However, the presence of an inwardly directed proton gradient enhances choline uptake (By similarity). Also acts as a heme b transporter (PubMed:20823265, PubMed:32973183). Required to regulate mitochondrial respiration processes, ATP synthesis and thermogenesis (PubMed:32973183). At low heme levels, interacts with components of electron transfer chain (ETC) complexes and ATP2A2, leading to ubiquitin-mediated degradation of ATP2A2 and inhibition of thermogenesis (PubMed:32973183). Upon heme binding, dissociates from ETC complexes to allow switching from mitochondrial ATP synthesis to thermogenesis (PubMed:32973183)","subcellular_location":"Cell membrane; Mitochondrion membrane; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q9UPI3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FLVCR2","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FLVCR2","total_profiled":1310},"omim":[{"mim_id":"610865","title":"FLVCR HEME TRANSPORTER 2; FLVCR2","url":"https://www.omim.org/entry/610865"},{"mim_id":"609144","title":"FLVCR HEME TRANSPORTER 1; FLVCR1","url":"https://www.omim.org/entry/609144"},{"mim_id":"225790","title":"PROLIFERATIVE VASCULOPATHY AND HYDRANENCEPHALY-HYDROCEPHALY SYNDROME; PVHH","url":"https://www.omim.org/entry/225790"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"choroid plexus","ntpm":28.5}],"url":"https://www.proteinatlas.org/search/FLVCR2"},"hgnc":{"alias_symbol":["FLJ20371","MFSD7C","SLC49A2","CCT"],"prev_symbol":["C14orf58"]},"alphafold":{"accession":"Q9UPI3","domains":[{"cath_id":"1.20.1250.20","chopping":"80-281","consensus_level":"medium","plddt":91.1146,"start":80,"end":281},{"cath_id":"1.20.1250.20","chopping":"299-508","consensus_level":"medium","plddt":91.2796,"start":299,"end":508}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UPI3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UPI3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UPI3-F1-predicted_aligned_error_v6.png","plddt_mean":80.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FLVCR2","jax_strain_url":"https://www.jax.org/strain/search?query=FLVCR2"},"sequence":{"accession":"Q9UPI3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UPI3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UPI3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UPI3"}},"corpus_meta":[{"pmid":"11080144","id":"PMC_11080144","title":"Eukaryotic 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research","url":"https://pubmed.ncbi.nlm.nih.gov/29913154","citation_count":26,"is_preprint":false},{"pmid":"32369453","id":"PMC_32369453","title":"Lack of Flvcr2 impairs brain angiogenesis without affecting the blood-brain barrier.","date":"2020","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/32369453","citation_count":25,"is_preprint":false},{"pmid":"33072568","id":"PMC_33072568","title":"Upregulation of CCT-3 Induces Breast Cancer Cell Proliferation Through miR-223 Competition and Wnt/β-Catenin Signaling Pathway Activation.","date":"2020","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33072568","citation_count":25,"is_preprint":false},{"pmid":"33996588","id":"PMC_33996588","title":"Chaperonin-Containing TCP1 Complex (CCT) Promotes Breast Cancer Growth Through Correlations With Key Cell Cycle Regulators.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33996588","citation_count":25,"is_preprint":false},{"pmid":"32369449","id":"PMC_32369449","title":"Deficiency of MFSD7c results in microcephaly-associated vasculopathy in Fowler syndrome.","date":"2020","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/32369449","citation_count":24,"is_preprint":false},{"pmid":"20890741","id":"PMC_20890741","title":"Interactions between the actin filament capping and severing protein gelsolin and the molecular chaperone CCT: evidence for nonclassical substrate interactions.","date":"2010","source":"Cell stress & chaperones","url":"https://pubmed.ncbi.nlm.nih.gov/20890741","citation_count":23,"is_preprint":false},{"pmid":"37193829","id":"PMC_37193829","title":"Pathway and mechanism of tubulin folding mediated by TRiC/CCT along its ATPase cycle revealed using cryo-EM.","date":"2023","source":"Communications 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cell","url":"https://pubmed.ncbi.nlm.nih.gov/27708139","citation_count":20,"is_preprint":false},{"pmid":"22133715","id":"PMC_22133715","title":"Reconstitution of the human chaperonin CCT by co-expression of the eight distinct subunits in mammalian cells.","date":"2011","source":"Protein expression and purification","url":"https://pubmed.ncbi.nlm.nih.gov/22133715","citation_count":20,"is_preprint":false},{"pmid":"8573069","id":"PMC_8573069","title":"Cloning, structure and mRNA expression of human Cctg, which encodes the chaperonin subunit CCT gamma.","date":"1996","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/8573069","citation_count":19,"is_preprint":false},{"pmid":"9450343","id":"PMC_9450343","title":"Developmental and light-dependent changes of the cytosolic chaperonin containing TCP-1 (CCT) subunits in maize seedlings, and the localization in coleoptiles.","date":"1997","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9450343","citation_count":19,"is_preprint":false},{"pmid":"38168070","id":"PMC_38168070","title":"STYXL1 regulates CCT complex assembly and flagellar tubulin folding in sperm formation.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38168070","citation_count":18,"is_preprint":false},{"pmid":"31400757","id":"PMC_31400757","title":"Targeting β-tubulin/CCT-β complex induces apoptosis and suppresses migration and invasion of highly metastatic lung adenocarcinoma.","date":"2020","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/31400757","citation_count":18,"is_preprint":false},{"pmid":"26364302","id":"PMC_26364302","title":"The molecular chaperone CCT modulates the activity of the actin filament severing and capping protein gelsolin in vitro.","date":"2015","source":"Cell stress & chaperones","url":"https://pubmed.ncbi.nlm.nih.gov/26364302","citation_count":18,"is_preprint":false},{"pmid":"36196890","id":"PMC_36196890","title":"Mechanistic insights into protein folding by the eukaryotic chaperonin complex CCT.","date":"2022","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/36196890","citation_count":17,"is_preprint":false},{"pmid":"36921056","id":"PMC_36921056","title":"Structural basis of plp2-mediated cytoskeletal protein folding by TRiC/CCT.","date":"2023","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/36921056","citation_count":17,"is_preprint":false},{"pmid":"33731457","id":"PMC_33731457","title":"Human Papillomavirus infection requires the CCT Chaperonin Complex.","date":"2021","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/33731457","citation_count":17,"is_preprint":false},{"pmid":"28906489","id":"PMC_28906489","title":"Disrupting CCT-β : β-tubulin selectively kills CCT-β overexpressed cancer cells through MAPKs activation.","date":"2017","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/28906489","citation_count":17,"is_preprint":false},{"pmid":"38302740","id":"PMC_38302740","title":"MFSD7c functions as a transporter of choline at the blood-brain barrier.","date":"2024","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/38302740","citation_count":16,"is_preprint":false},{"pmid":"37625406","id":"PMC_37625406","title":"A hierarchical assembly pathway directs the unique subunit arrangement of TRiC/CCT.","date":"2023","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/37625406","citation_count":16,"is_preprint":false},{"pmid":"32316208","id":"PMC_32316208","title":"Genome-Wide Identification, Expression Analysis and Functional Study of CCT Gene Family in Medicago truncatula.","date":"2020","source":"Plants (Basel, 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/18775504","citation_count":15,"is_preprint":false},{"pmid":"9434769","id":"PMC_9434769","title":"Subunit characterization of the Caenorhabditis elegans chaperonin containing TCP-1 and expression pattern of the gene encoding CCT-1.","date":"1997","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9434769","citation_count":15,"is_preprint":false},{"pmid":"34312216","id":"PMC_34312216","title":"CCT and CCT-Like Modular Protein Interaction Domains in WNK Signaling.","date":"2021","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34312216","citation_count":14,"is_preprint":false},{"pmid":"31410727","id":"PMC_31410727","title":"Co-expression of CCT subunits hints at TRiC assembly.","date":"2019","source":"Cell stress & chaperones","url":"https://pubmed.ncbi.nlm.nih.gov/31410727","citation_count":14,"is_preprint":false},{"pmid":"36292714","id":"PMC_36292714","title":"Genome-Wide Identification and Characterization of the CCT Gene Family in Foxtail Millet (Setaria italica) Response to Diurnal Rhythm and Abiotic Stress.","date":"2022","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/36292714","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":45003,"output_tokens":2827,"usd":0.088707,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9903,"output_tokens":2920,"usd":0.061257,"stage2_stop_reason":"end_turn"},"total_usd":0.149964,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the corpus, I need to identify papers specifically about FLVCR2 (also known as MFSD7C, SLC49A2, CCT [as an alias for this gene], FLJ20371, C14orf58).\n\nThe vast majority of papers (1-9, 11-30, etc.) are about the chaperonin CCT/TRiC complex — a completely different protein family. The \"CCT\" alias for FLVCR2 is not the same as the chaperonin CCT. Papers about chaperonin CCT/TRiC must be excluded as symbol collisions.\n\nRelevant papers about FLVCR2/MFSD7C: 10, 32, 50, 53, 63, 64, 69, 72, 76, 91.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"FLVCR2 functions as an importer of heme: it binds hemin-conjugated agarose (competed by free hemin), and mammalian cells and Xenopus oocytes expressing FLVCR2 display enhanced heme uptake. siRNA knockdown of FLVCR2 or binding of FY981 FeLV envelope protein to FLVCR2 reduces heme import. Cells overexpressing FLVCR2 show increased sensitivity to heme toxicity consistent with enhanced uptake.\",\n      \"method\": \"Hemin-agarose pulldown, heterologous expression in Xenopus oocytes and mammalian cells with radiolabeled heme uptake assays, siRNA knockdown, retroviral envelope competition\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (binding assay, functional uptake in two heterologous systems, siRNA, competitive inhibition) in a single rigorous study establishing transporter function\",\n      \"pmids\": [\"20823265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FLVCR2 functions as a cell-surface receptor for the FY981 feline leukemia virus (FeLV), enabling viral infection of porcine ST-IOWA cells that are resistant to both FeLV-A and FeLV-C; FLVCR2 is distinct from but related to FLVCR1.\",\n      \"method\": \"Pseudotype virus infection assays across multiple cell lines; receptor identification by functional complementation and competition\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional infection assays in multiple cell types in one study, but receptor identity inferred primarily from infection phenotype without direct binding reconstitution\",\n      \"pmids\": [\"19369334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Loss-of-function mutations in FLVCR2 cause Fowler syndrome (proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome), an autosomal recessive prenatal lethal disorder; five distinct germline mutations identified by autozygosity mapping and direct sequencing in five families, establishing FLVCR2 as the causative gene.\",\n      \"method\": \"Autozygosity mapping (SNP microarray), microsatellite genotyping, direct sequencing of candidate genes in consanguineous families\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mapping with multiple independent families establishes disease causation, but mechanism is inferred rather than directly reconstituted\",\n      \"pmids\": [\"20206334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FLVCR2 mutations (including a large deletion) were identified in lethal cerebral vasculopathy (Fowler syndrome/PGV); absence of alpha-smooth muscle actin immunostaining in abnormal fetal PGV brain vessels suggests a deficit in pericytes essential for capillary stabilization during brain angiogenesis.\",\n      \"method\": \"High-throughput sequencing of a 4.1 Mb linkage interval after sequence capture; immunostaining of fetal brain tissue\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — HTS-based gene identification in multiple families plus histological phenotyping; pericyte deficit is an observed correlate, not experimentally manipulated\",\n      \"pmids\": [\"20690116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MFSD7C (FLVCR2) uncouples mitochondrial respiration to switch ATP synthesis to thermogenesis in response to heme. When heme levels are low, MFSD7C promotes ATP synthesis by interacting with components of electron transport chain (ETC) complexes III, IV, and V and destabilizing SERCA2b. Upon heme binding to the N-terminal domain, MFSD7C dissociates from ETC components and SERCA2b, resulting in SERCA2b stabilization and thermogenesis.\",\n      \"method\": \"Co-immunoprecipitation with ETC components, heme-binding assays to N-terminal domain, functional measurement of ATP synthesis vs. thermogenesis, SERCA2b stability assays, loss-of-function studies\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP with ETC components, domain-level heme binding, functional metabolic readouts (ATP vs. heat), and mechanistic dissection of heme-regulated conformational switch in one rigorous study\",\n      \"pmids\": [\"32973183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Flvcr2 (Mfsd7c) is required for angiogenic sprouting in the brain but is dispensable for blood-brain barrier maintenance. Endothelial cells lacking Flvcr2 fail to adopt tip cell properties, show altered expression of angiogenic factors, and display reduced sprouting, leading to glomeruloid vascular malformations, brain hypovascularization, hypoxia, and hydrocephalus in mice.\",\n      \"method\": \"Conditional and global Flvcr2 knockout mice; analysis of vascular morphology, tip cell markers, angiogenic factor expression, BBB integrity assays, histology\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with multiple defined cellular phenotypes (tip cell failure, sprouting defect, BBB integrity uncoupling) establishing pathway position in brain angiogenesis\",\n      \"pmids\": [\"32369453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Global knockout of Mfsd7c (FLVCR2) in mice results in late-gestation lethality with inhibited angiogenic growth of CNS blood vessels, dilated and fused vascular tips forming glomeruloid vessels, reduced cerebral cortical layers, enlarged ventricles, and microcephaly; transcriptomic analysis revealed upregulation of genes in glycolysis and angiogenesis pathways, and brain hypoxia with neuronal cell death.\",\n      \"method\": \"Global Mfsd7c knockout mice; histology, transcriptomics, hypoxia marker staining, comparison with human FLVCR2 mutation phenotypes\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple orthogonal phenotypic and molecular readouts; independently replicates vascular phenotype seen in human Fowler syndrome\",\n      \"pmids\": [\"32369449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FLVCR2 is a blood-brain barrier choline transporter responsible for the majority of choline uptake into the brain. Cryo-EM structures of choline-bound FLVCR2 in both inward-facing and outward-facing states reveal that choline binds within an aromatic cage. In vivo and in vitro experiments confirm FLVCR2-mediated choline import at the BBB.\",\n      \"method\": \"Cryo-EM structure determination (inward- and outward-facing states), in vivo choline uptake studies in mice, in vitro transport assays, aromatic cage identification by structural analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — near-atomic cryo-EM structures in two conformational states plus in vivo and in vitro functional validation; establishes molecular mechanism of choline binding and transport\",\n      \"pmids\": [\"38693257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MFSD7c (FLVCR2) functions as a facilitative choline transporter at the blood-brain barrier; choline uptake is electrogenic (shown by patch clamp), greatly enhanced by choline-metabolizing enzymes, and conserved in vertebrates but not yeast. MFSD7c is a functional ortholog of the yeast choline importer HNM1. Missense mutations from Fowler syndrome patients abolish or reduce choline transport activity. Endothelial-specific KO suppresses exogenous choline import from blood but paradoxically increases brain choline levels via impaired export of choline derived from lysophosphatidylcholine.\",\n      \"method\": \"Cell-based choline uptake assays, metabolomics of Mfsd7c-/- embryo brains and livers, single-cell patch clamp electrophysiology, stable-isotope tracing, endothelial-specific KO mice, functional complementation of yeast HNM1 mutant, patient mutation functional analysis\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (electrophysiology, isotope tracing, metabolomics, genetic KO, heterologous complementation, patient mutation testing) establishing transport mechanism and direction\",\n      \"pmids\": [\"38302740\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FLVCR2 (MFSD7C/SLC49A2) is a 12-transmembrane major facilitator superfamily transporter expressed at the blood-brain barrier endothelium that primarily mediates choline transport into (and export of lysophosphatidylcholine-derived choline out of) the brain via an aromatic-cage binding site, as revealed by cryo-EM structures in inward- and outward-facing states; it also binds heme and, in response to heme, uncouples mitochondrial respiration from ATP synthesis to thermogenesis by dissociating from ETC complexes III/IV/V and stabilizing SERCA2b; loss-of-function mutations cause Fowler syndrome through failure of brain endothelial tip-cell-mediated angiogenic sprouting, leading to glomeruloid vasculopathy, hydrocephalus, and prenatal lethality.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FLVCR2 (MFSD7C/SLC49A2) is a multi-pass major facilitator superfamily transporter that governs choline supply to the brain and is essential for cerebral angiogenesis [#7, #5]. It is the principal blood-brain barrier choline importer: cryo-EM structures captured in inward- and outward-facing states show choline bound within an aromatic cage, and in vivo and in vitro assays confirm FLVCR2-mediated choline uptake [#7]. Transport is facilitative and electrogenic, enhanced by downstream choline-metabolizing enzymes, and functionally conserved to the extent that FLVCR2 complements the yeast choline importer HNM1; beyond import from blood, it also mediates export of lysophosphatidylcholine-derived choline, such that endothelial loss paradoxically raises brain choline [#8]. The same transporter binds heme and was independently characterized as a heme importer whose overexpression sensitizes cells to heme toxicity [#0], and at the mitochondrion heme binding to its N-terminal domain triggers dissociation from electron transport chain complexes III/IV/V and stabilization of SERCA2b, switching respiration from ATP synthesis toward thermogenesis [#4]. FLVCR2 is required for endothelial tip-cell formation and angiogenic sprouting in the CNS but dispensable for blood-brain barrier maintenance; its loss produces glomeruloid vascular malformations, brain hypovascularization, hypoxia, and hydrocephalus [#5, #6]. Loss-of-function mutations in FLVCR2 cause autosomal recessive, prenatally lethal Fowler syndrome (proliferative vasculopathy with hydranencephaly-hydrocephaly), and patient missense mutations abolish or reduce choline transport activity [#2, #8]. FLVCR2 also serves as a cell-surface entry receptor for FY981 feline leukemia virus [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Identification of FLVCR2 as a functional receptor answered what cell-surface molecule mediates FY981 FeLV entry, distinguishing it from the related FLVCR1.\",\n      \"evidence\": \"Pseudotype virus infection and functional complementation across resistant and permissive cell lines\",\n      \"pmids\": [\"19369334\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor role inferred from infection phenotype without direct virus-protein binding reconstitution\", \"Relationship between viral receptor function and physiological transport activity not addressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating heme binding and heme uptake established a biochemical transport activity for FLVCR2, framing it as a heme importer.\",\n      \"evidence\": \"Hemin-agarose pulldown with free-hemin competition, radiolabeled heme uptake in Xenopus oocytes and mammalian cells, siRNA knockdown, and FeLV envelope competition\",\n      \"pmids\": [\"20823265\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the physiological substrate in vivo\", \"Direction and tissue context of heme transport not resolved\", \"Relationship of heme handling to later-identified choline transport unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Genetic mapping in consanguineous families answered whether FLVCR2 is a disease gene, establishing it as the cause of Fowler syndrome and linking it to brain vascular development.\",\n      \"evidence\": \"Autozygosity mapping, targeted/high-throughput sequencing, and fetal brain immunostaining across multiple families\",\n      \"pmids\": [\"20206334\", \"20690116\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Disease mechanism inferred genetically rather than reconstituted\", \"Pericyte/smooth-muscle-actin deficit was an observed correlate, not experimentally manipulated\", \"How loss of transport activity produces vasculopathy unaddressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Conditional and global knockout mice answered where FLVCR2 acts in the vasculature, showing it is required for endothelial tip-cell formation and CNS angiogenic sprouting but not for blood-brain barrier maintenance, and that loss recapitulates the human glomeruloid vasculopathy.\",\n      \"evidence\": \"Conditional and global Flvcr2/Mfsd7c knockout mice with vascular morphology, tip-cell markers, transcriptomics, hypoxia staining, and BBB integrity assays\",\n      \"pmids\": [\"32369453\", \"32369449\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular substrate driving the angiogenic phenotype not defined\", \"Mechanism linking transporter activity to tip-cell gene expression unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mechanistic dissection at the mitochondrion answered how heme regulates FLVCR2, revealing a heme-triggered conformational switch that uncouples respiration toward thermogenesis.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation with ETC complexes III/IV/V, N-terminal-domain heme-binding assays, SERCA2b stability assays, and ATP-versus-heat functional readouts\",\n      \"pmids\": [\"32973183\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How mitochondrial thermogenic role integrates with plasma-membrane transport function not reconciled\", \"Physiological relevance to brain vascular phenotype not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cryo-EM structures and functional validation answered the molecular identity of FLVCR2's principal physiological substrate, defining it as the blood-brain barrier choline transporter and resolving the choline-binding aromatic cage in two conformational states.\",\n      \"evidence\": \"Cryo-EM in inward- and outward-facing states, in vivo mouse choline uptake, in vitro transport assays, patch-clamp electrophysiology, stable-isotope tracing, metabolomics, endothelial-specific KO, yeast HNM1 complementation, and patient-mutation testing\",\n      \"pmids\": [\"38693257\", \"38302740\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How choline transport mechanistically drives angiogenic sprouting not resolved\", \"Relationship between choline transport and the separately reported heme functions unintegrated\", \"Energetic coupling of the facilitative/electrogenic cycle only partly defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how FLVCR2's choline transport, heme handling, and mitochondrial thermogenic activities are mechanistically reconciled within one protein, and how transport activity is causally linked to endothelial tip-cell behavior and Fowler syndrome pathology.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified model connecting substrate transport to the angiogenic and disease phenotypes\", \"Subcellular partitioning between plasma membrane and mitochondrion not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 7, 8]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SERCA2b\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}