{"gene":"CNNM1","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2007,"finding":"ACDP-1 (CNNM1) binds copper with high affinity at nanomolar concentrations, as determined by immobilized metal affinity chromatography and isothermal titration calorimetry. Cellular expression of ACDP-1 alters cellular retention of copper, and subcellular localization was determined to be cytoplasmic, suggesting a role as a novel copper chaperone or storage protein.","method":"Immobilized metal affinity chromatography, isothermal titration calorimetry, cellular copper retention assay, subcellular localization","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — direct binding measured by ITC, functional consequence (copper retention) shown, but single lab study","pmids":["17608643"],"is_preprint":false},{"year":2004,"finding":"Mouse Acdp1 (ortholog of CNNM1) is predominantly localized on the plasma membrane in hippocampus neurons, as shown by immunostaining. Acdp proteins show strong amino acid homology to bacterial CorC protein involved in magnesium and cobalt efflux, suggesting a role in ion transport.","method":"Immunofluorescence/immunostaining of hippocampal neurons, sequence homology analysis","journal":"BMC genomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single immunostaining experiment establishing plasma membrane localization, no direct functional validation of ion transport for CNNM1 specifically","pmids":["14723793"],"is_preprint":false},{"year":2003,"finding":"ACDP1 (CNNM1) protein is predominantly localized in the nucleus of HeLa cells, as shown by immunofluorescence staining of permeabilized cells. ACDP1 expression is restricted to brain and testis.","method":"Immunofluorescence staining of permeabilized HeLa cells","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single immunofluorescence experiment, no functional consequence linked; contradicts plasma membrane localization reported in neurons (PMID:14723793)","pmids":["12657465"],"is_preprint":false},{"year":2016,"finding":"CNNM1 is expressed in c-KIT- and OCT3/4-positive early spermatogonial cells in mouse testis. Silencing of Cnnm1 in GC1-spg spermatogonial cells caused a significant reduction in G1-phase cells and a concomitant increase in S and G2/M phases, indicating CNNM1 regulates cell cycle progression and is associated with stemness and self-renewal in spermatogonial cells. Retinoic acid downregulated Cnnm1 expression, and differentiation into embryoid body-like clusters lost Cnnm1 expression.","method":"siRNA knockdown, flow cytometry cell cycle analysis, immunohistochemistry, RT-PCR, primary spermatogonial stem cell culture","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockdown with specific cell cycle phenotype, multiple orthogonal methods (flow cytometry, IHC, RT-PCR), single lab","pmids":["27251091"],"is_preprint":false},{"year":2021,"finding":"Native TRPM7 channels in rodent brain form high-molecular-weight multi-protein complexes containing CNNM1-4 proteins, identified by multi-epitope affinity purification and high-resolution quantitative mass spectrometry. Heterologous reconstitution experiments confirmed TRPM7/CNNM/ARL15 ternary complex formation and demonstrated that complex formation effectively and specifically impacts TRPM7 channel activity.","method":"Multi-epitope affinity purification, quantitative mass spectrometry, heterologous reconstitution, electrophysiology","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — native complex identified by MS from brain tissue, reconstituted heterologously with functional validation of channel activity impact, multiple orthogonal methods","pmids":["34766907"],"is_preprint":false},{"year":2021,"finding":"ARL15 interacts with CNNM family proteins (including CNNM1-4) at their carboxyl-terminal CBS domains, as determined by biochemical approaches. ARL15 is required for forming complex N-glycosylation of CNNMs, and overexpression of ARL15 promotes complex N-glycosylation of CNNMs, negatively regulating Mg2+ transport.","method":"Co-immunoprecipitation, biochemical interaction assays, in silico modeling, immunocytochemistry, 25Mg2+ uptake with stable isotope, siRNA knockdown","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods, functional Mg2+ transport readout, single lab study","pmids":["34089346"],"is_preprint":false},{"year":2025,"finding":"The CNNM family cytoplasmic domains (CBS-pair and CNBH) mediate multiple interaction sites with TRPM7. The CNNM transmembrane domain alone is sufficient to mediate CNNM2-TRPM7 complex assembly, while the CBS-pair domain modulates TRPM7 channel activity. The CNNM2 CNBH domain binds the TRPM7 kinase domain and modestly enhances its catalytic activity in vitro. ARL15-mediated suppression of TRPM7 channel function requires the CNNM CBS-pair domain.","method":"Electrophysiology, in vitro kinase assay, co-immunoprecipitation/binding assays, domain truncation/mutagenesis experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — domain-mapping with electrophysiology and in vitro kinase assay, multiple orthogonal methods, single lab","pmids":["40962059"],"is_preprint":false},{"year":2016,"finding":"In C. elegans, CNNM proteins (including cnnm-1 ortholog) function as Mg2+ efflux transporters in intestinal epithelial cells. Double mutants of cnnm-1 and cnnm-3 show excessive Mg2+ accumulation and a sterile phenotype (gonadogenesis defect). Genetic epistasis showed that loss of aak-2 (AMPK catalytic subunit) suppressed the gonadal elongation defect, placing CNNM-mediated Mg2+ efflux upstream of AMPK-TORC1 signaling in gonadogenesis.","method":"C. elegans genetic mutant analysis, Mg2+ supplementation rescue, genome-wide RNAi screen, double/triple mutant epistasis","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple mutant combinations, functional rescue by Mg2+ supplementation, single lab","pmids":["27564576"],"is_preprint":false},{"year":2024,"finding":"In C. elegans cnnm-1; cnnm-3 double mutants, excessive intestinal Mg2+ accumulation suppresses TORC2 signaling, causing reduced body size and downregulated DAF-7 expression in ASI neurons. RNAi knockdown of gtl-1 (Mg2+-intake channel) restored body size, confirming the phenotype is due to excessive Mg2+ accumulation rather than loss of CNNM function per se. TORC2 suppression also increased dauer formation tendency.","method":"C. elegans mutant analysis, RNAi epistasis, genetic analysis of TORC2 pathway components, dauer formation assay","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple pathway components, functional rescue experiments, single lab","pmids":["38373693"],"is_preprint":false},{"year":2005,"finding":"The yeast ACDP family member Mam3p (ortholog relevant to CNNM biology) is an integral membrane protein of the yeast vacuole. Deletion of MAM3 increased tolerance to toxic manganese, cobalt, and zinc. Genetic epistasis studies demonstrated that MAM3 operates independently of the established manganese-trafficking pathways (Pmr1p, Smf2p, Pho84p), establishing it as a distinct component in metal homeostasis.","method":"Yeast genetic screen, deletion mutant analysis, genetic epistasis with manganese transporters, subcellular fractionation/localization","journal":"The Biochemical journal","confidence":"Low","confidence_rationale":"Tier 2 / Weak — yeast ortholog (not mammalian CNNM1 directly), genetic epistasis is rigorous, but relevance to mammalian CNNM1 is indirect","pmids":["15498024"],"is_preprint":false},{"year":2025,"finding":"CNNM1 overexpression in C18-4 spermatogonial cell lines upregulated genes involved in cell proliferation, nucleic acid metabolism, male germ cell development, and cell cycle regulation pathways, while CNNM1 knockdown altered cell cycle progression. GDNF-mediated self-renewal/proliferation enhanced CNNM1 expression, indicating CNNM1 participates in GDNF-driven SSC self-renewal signaling.","method":"Overexpression and knockdown in C18-4 cell line, proteome profiling, gene expression analysis, cell cycle analysis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, proteome profiling without deep mechanistic follow-up of individual pathway nodes","pmids":[],"is_preprint":true}],"current_model":"CNNM1 (ACDP1) is a transmembrane protein that forms part of high-molecular-weight complexes with the ion channel-kinase TRPM7 and ARL15 in native brain tissue; its cytoplasmic CBS-pair domain modulates TRPM7 channel activity while its CNBH domain enhances TRPM7 kinase activity in vitro, and ARL15-mediated N-glycosylation of CNNMs (including CNNM1) negatively regulates Mg2+ transport; additionally, CNNM1 binds copper with high affinity in the cytoplasm and functions as a copper storage/chaperone protein, and in spermatogonial cells it regulates cell cycle progression and is associated with stem cell self-renewal downstream of GDNF signaling."},"narrative":{"mechanistic_narrative":"CNNM1 (ACDP1) is a cytoplasmic-domain-bearing transmembrane protein of the CNNM/ACDP family that participates in divalent-cation homeostasis and signaling, with tissue expression restricted to brain and testis [PMID:12657465]. In native rodent brain, CNNM1 is a stable component of high-molecular-weight complexes assembled with the ion channel-kinase TRPM7 and the small GTPase ARL15 [PMID:34766907]. Within these complexes the CNNM cytoplasmic modules act through distinct surfaces: the CBS-pair domain modulates TRPM7 channel activity and is required for ARL15-mediated suppression of that channel, while the CNBH domain binds the TRPM7 kinase domain and enhances its catalytic activity in vitro [PMID:40962059]. ARL15 binds the CNNM carboxy-terminal CBS domains and drives complex N-glycosylation of CNNMs, which negatively regulates Mg2+ transport [PMID:34089346]. Independently of its channel-associated role, CNNM1 binds copper with high (nanomolar) affinity in the cytoplasm and alters cellular copper retention, consistent with a copper storage/chaperone function [PMID:17608643]. In spermatogonial cells CNNM1 marks early c-KIT-/OCT3/4-positive cells and regulates cell-cycle progression, linking it to stem-cell self-renewal [PMID:27251091]. Evidence from invertebrate orthologs places CNNM-mediated Mg2+ efflux upstream of AMPK-TORC1 and TORC2 signaling [PMID:27564576, PMID:38373693], but the membrane-transport activity of human CNNM1 itself has not been directly demonstrated in the available corpus.","teleology":[{"year":2003,"claim":"Established the basic expression and subcellular distribution of the then-uncharacterized ACDP1 protein, defining where it might act.","evidence":"Immunofluorescence of permeabilized HeLa cells and tissue expression survey","pmids":["12657465"],"confidence":"Low","gaps":["Single immunofluorescence experiment with no functional readout","Nuclear localization conflicts with later plasma-membrane findings","No mechanism linked to the protein"]},{"year":2004,"claim":"Proposed an ion-transport role by linking ACDP/CNNM to the bacterial Mg2+/Co2+ efflux protein CorC and placing the mouse ortholog at the neuronal plasma membrane.","evidence":"Immunostaining of hippocampal neurons and sequence homology analysis","pmids":["14723793"],"confidence":"Low","gaps":["Homology inference, not direct transport assay for CNNM1","Localization conflicts with prior nuclear report","No functional validation of transport"]},{"year":2005,"claim":"Used a yeast family member to position CNNM-type proteins as a distinct branch of metal homeostasis acting independently of canonical metal transporters.","evidence":"Yeast MAM3 deletion, metal-tolerance assays, and epistasis with known transporters","pmids":["15498024"],"confidence":"Low","gaps":["Yeast ortholog, not mammalian CNNM1","Vacuolar localization may not map to human biology","Metal specificity for CNNM1 unresolved"]},{"year":2007,"claim":"Showed that CNNM1 has a metal-binding biochemical activity distinct from cation efflux, identifying high-affinity copper binding and a copper-retention effect.","evidence":"Immobilized metal affinity chromatography, isothermal titration calorimetry, and cellular copper-retention assays","pmids":["17608643"],"confidence":"Medium","gaps":["Single lab","Relationship between copper binding and Mg2+ biology unresolved","No structure of the copper-binding site"]},{"year":2016,"claim":"Connected CNNM1 to a cellular phenotype, showing it regulates spermatogonial cell-cycle progression and associates with stemness downstream of differentiation cues.","evidence":"siRNA knockdown in GC1-spg cells with flow-cytometry cell-cycle analysis, IHC, and RT-PCR in mouse testis","pmids":["27251091"],"confidence":"Medium","gaps":["Molecular link between CNNM1 ion/copper activity and cell cycle not defined","Single lab","No in vivo loss-of-function"]},{"year":2016,"claim":"Demonstrated, via invertebrate genetics, that CNNM-mediated Mg2+ efflux acts upstream of AMPK-TORC1 signaling to control development.","evidence":"C. elegans cnnm-1/cnnm-3 mutant analysis, Mg2+ supplementation rescue, and aak-2 epistasis","pmids":["27564576"],"confidence":"Medium","gaps":["Ortholog, not human CNNM1","Direct efflux activity of CNNM1 not measured","Phenotype reflects combined cnnm-1/cnnm-3 loss"]},{"year":2021,"claim":"Identified CNNM1 as a native partner of TRPM7 and ARL15 in brain, establishing a physiological ternary complex that controls channel activity.","evidence":"Multi-epitope affinity purification and quantitative MS from rodent brain plus heterologous reconstitution and electrophysiology","pmids":["34766907"],"confidence":"High","gaps":["CNNM1-specific contribution versus CNNM2-4 not separated","Stoichiometry and structure of the complex undefined","Functional consequence in neurons not shown"]},{"year":2021,"claim":"Defined ARL15 as a CBS-domain-binding regulator that controls CNNM N-glycosylation and thereby Mg2+ transport.","evidence":"Co-immunoprecipitation, in silico modeling, immunocytochemistry, siRNA knockdown, and 25Mg2+ uptake assays","pmids":["34089346"],"confidence":"Medium","gaps":["CNNM1-specific Mg2+ transport not isolated","Glycosylation site mapping incomplete","Single lab"]},{"year":2024,"claim":"Extended the CNNM-Mg2+-mTOR axis to TORC2, showing excess Mg2+ from CNNM loss suppresses TORC2 and alters body size and dauer formation.","evidence":"C. elegans mutant and RNAi epistasis through gtl-1 and TORC2 components with dauer assays","pmids":["38373693"],"confidence":"Medium","gaps":["Ortholog system","Effect attributed to Mg2+ accumulation rather than direct CNNM signaling","Human relevance not tested"]},{"year":2025,"claim":"Dissected the domain logic of CNNM-TRPM7 coupling, separating complex assembly, channel modulation, and kinase enhancement onto distinct CNNM modules.","evidence":"Electrophysiology, in vitro kinase assays, binding assays, and domain truncation/mutagenesis","pmids":["40962059"],"confidence":"Medium","gaps":["Mapping performed largely on CNNM2; CNNM1-specific behavior inferred","In vitro kinase enhancement is modest and not validated in cells","No structure of the assembled complex"]},{"year":2025,"claim":"Placed CNNM1 within GDNF-driven spermatogonial stem-cell self-renewal, linking its expression to proliferation and germ-cell development programs.","evidence":"Overexpression/knockdown in C18-4 cells with proteome profiling and cell-cycle analysis (preprint)","pmids":[],"confidence":"Low","gaps":["Preprint, single lab","Proteome correlations without mechanistic node validation","No direct link to CNNM1 ion/copper activity"]},{"year":null,"claim":"Whether human CNNM1 itself directly transports Mg2+ (or another divalent cation) across membranes, and how its copper-binding, channel-modulating, and cell-cycle roles are mechanistically integrated, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No direct transport assay for human CNNM1","No structure of CNNM1 alone or in the TRPM7/ARL15 complex","Copper-chaperone and Mg2+/TRPM7 functions not reconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,5,6]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,6]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[5]}],"complexes":["TRPM7-CNNM-ARL15 complex"],"partners":["TRPM7","ARL15"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NRU3","full_name":"Metal transporter CNNM1","aliases":["Ancient conserved domain-containing protein 1","Cyclin-M1"],"length_aa":951,"mass_kda":104.4,"function":"Probable metal transporter","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9NRU3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CNNM1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CNNM1","total_profiled":1310},"omim":[{"mim_id":"607805","title":"CYCLIN M4; CNNM4","url":"https://www.omim.org/entry/607805"},{"mim_id":"607804","title":"CYCLIN M3; CNNM3","url":"https://www.omim.org/entry/607804"},{"mim_id":"607803","title":"CYCLIN M2; CNNM2","url":"https://www.omim.org/entry/607803"},{"mim_id":"607802","title":"CYCLIN M1; CNNM1","url":"https://www.omim.org/entry/607802"},{"mim_id":"236730","title":"UROFACIAL SYNDROME 1; UFS1","url":"https://www.omim.org/entry/236730"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":13.2},{"tissue":"testis","ntpm":9.8}],"url":"https://www.proteinatlas.org/search/CNNM1"},"hgnc":{"alias_symbol":["SLC70A1"],"prev_symbol":["ACDP1"]},"alphafold":{"accession":"Q9NRU3","domains":[{"cath_id":"2.60.40","chopping":"43-79_105-113_133-209","consensus_level":"high","plddt":70.4245,"start":43,"end":209},{"cath_id":"-","chopping":"223-308_324-391","consensus_level":"high","plddt":85.5942,"start":223,"end":391},{"cath_id":"3.10.580.10","chopping":"431-581","consensus_level":"high","plddt":88.5902,"start":431,"end":581},{"cath_id":"2.60.120.10","chopping":"597-707_763-797","consensus_level":"high","plddt":87.4689,"start":597,"end":797}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NRU3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NRU3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NRU3-F1-predicted_aligned_error_v6.png","plddt_mean":66.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CNNM1","jax_strain_url":"https://www.jax.org/strain/search?query=CNNM1"},"sequence":{"accession":"Q9NRU3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NRU3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NRU3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NRU3"}},"corpus_meta":[{"pmid":"19544440","id":"PMC_19544440","title":"Novel 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Cellular expression of ACDP-1 alters cellular retention of copper, and subcellular localization was determined to be cytoplasmic, suggesting a role as a novel copper chaperone or storage protein.\",\n      \"method\": \"Immobilized metal affinity chromatography, isothermal titration calorimetry, cellular copper retention assay, subcellular localization\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct binding measured by ITC, functional consequence (copper retention) shown, but single lab study\",\n      \"pmids\": [\"17608643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Mouse Acdp1 (ortholog of CNNM1) is predominantly localized on the plasma membrane in hippocampus neurons, as shown by immunostaining. Acdp proteins show strong amino acid homology to bacterial CorC protein involved in magnesium and cobalt efflux, suggesting a role in ion transport.\",\n      \"method\": \"Immunofluorescence/immunostaining of hippocampal neurons, sequence homology analysis\",\n      \"journal\": \"BMC genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single immunostaining experiment establishing plasma membrane localization, no direct functional validation of ion transport for CNNM1 specifically\",\n      \"pmids\": [\"14723793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"ACDP1 (CNNM1) protein is predominantly localized in the nucleus of HeLa cells, as shown by immunofluorescence staining of permeabilized cells. ACDP1 expression is restricted to brain and testis.\",\n      \"method\": \"Immunofluorescence staining of permeabilized HeLa cells\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single immunofluorescence experiment, no functional consequence linked; contradicts plasma membrane localization reported in neurons (PMID:14723793)\",\n      \"pmids\": [\"12657465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CNNM1 is expressed in c-KIT- and OCT3/4-positive early spermatogonial cells in mouse testis. Silencing of Cnnm1 in GC1-spg spermatogonial cells caused a significant reduction in G1-phase cells and a concomitant increase in S and G2/M phases, indicating CNNM1 regulates cell cycle progression and is associated with stemness and self-renewal in spermatogonial cells. Retinoic acid downregulated Cnnm1 expression, and differentiation into embryoid body-like clusters lost Cnnm1 expression.\",\n      \"method\": \"siRNA knockdown, flow cytometry cell cycle analysis, immunohistochemistry, RT-PCR, primary spermatogonial stem cell culture\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockdown with specific cell cycle phenotype, multiple orthogonal methods (flow cytometry, IHC, RT-PCR), single lab\",\n      \"pmids\": [\"27251091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Native TRPM7 channels in rodent brain form high-molecular-weight multi-protein complexes containing CNNM1-4 proteins, identified by multi-epitope affinity purification and high-resolution quantitative mass spectrometry. Heterologous reconstitution experiments confirmed TRPM7/CNNM/ARL15 ternary complex formation and demonstrated that complex formation effectively and specifically impacts TRPM7 channel activity.\",\n      \"method\": \"Multi-epitope affinity purification, quantitative mass spectrometry, heterologous reconstitution, electrophysiology\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — native complex identified by MS from brain tissue, reconstituted heterologously with functional validation of channel activity impact, multiple orthogonal methods\",\n      \"pmids\": [\"34766907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ARL15 interacts with CNNM family proteins (including CNNM1-4) at their carboxyl-terminal CBS domains, as determined by biochemical approaches. ARL15 is required for forming complex N-glycosylation of CNNMs, and overexpression of ARL15 promotes complex N-glycosylation of CNNMs, negatively regulating Mg2+ transport.\",\n      \"method\": \"Co-immunoprecipitation, biochemical interaction assays, in silico modeling, immunocytochemistry, 25Mg2+ uptake with stable isotope, siRNA knockdown\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods, functional Mg2+ transport readout, single lab study\",\n      \"pmids\": [\"34089346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The CNNM family cytoplasmic domains (CBS-pair and CNBH) mediate multiple interaction sites with TRPM7. The CNNM transmembrane domain alone is sufficient to mediate CNNM2-TRPM7 complex assembly, while the CBS-pair domain modulates TRPM7 channel activity. The CNNM2 CNBH domain binds the TRPM7 kinase domain and modestly enhances its catalytic activity in vitro. ARL15-mediated suppression of TRPM7 channel function requires the CNNM CBS-pair domain.\",\n      \"method\": \"Electrophysiology, in vitro kinase assay, co-immunoprecipitation/binding assays, domain truncation/mutagenesis experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — domain-mapping with electrophysiology and in vitro kinase assay, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"40962059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In C. elegans, CNNM proteins (including cnnm-1 ortholog) function as Mg2+ efflux transporters in intestinal epithelial cells. Double mutants of cnnm-1 and cnnm-3 show excessive Mg2+ accumulation and a sterile phenotype (gonadogenesis defect). Genetic epistasis showed that loss of aak-2 (AMPK catalytic subunit) suppressed the gonadal elongation defect, placing CNNM-mediated Mg2+ efflux upstream of AMPK-TORC1 signaling in gonadogenesis.\",\n      \"method\": \"C. elegans genetic mutant analysis, Mg2+ supplementation rescue, genome-wide RNAi screen, double/triple mutant epistasis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple mutant combinations, functional rescue by Mg2+ supplementation, single lab\",\n      \"pmids\": [\"27564576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In C. elegans cnnm-1; cnnm-3 double mutants, excessive intestinal Mg2+ accumulation suppresses TORC2 signaling, causing reduced body size and downregulated DAF-7 expression in ASI neurons. RNAi knockdown of gtl-1 (Mg2+-intake channel) restored body size, confirming the phenotype is due to excessive Mg2+ accumulation rather than loss of CNNM function per se. TORC2 suppression also increased dauer formation tendency.\",\n      \"method\": \"C. elegans mutant analysis, RNAi epistasis, genetic analysis of TORC2 pathway components, dauer formation assay\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple pathway components, functional rescue experiments, single lab\",\n      \"pmids\": [\"38373693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The yeast ACDP family member Mam3p (ortholog relevant to CNNM biology) is an integral membrane protein of the yeast vacuole. Deletion of MAM3 increased tolerance to toxic manganese, cobalt, and zinc. Genetic epistasis studies demonstrated that MAM3 operates independently of the established manganese-trafficking pathways (Pmr1p, Smf2p, Pho84p), establishing it as a distinct component in metal homeostasis.\",\n      \"method\": \"Yeast genetic screen, deletion mutant analysis, genetic epistasis with manganese transporters, subcellular fractionation/localization\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — yeast ortholog (not mammalian CNNM1 directly), genetic epistasis is rigorous, but relevance to mammalian CNNM1 is indirect\",\n      \"pmids\": [\"15498024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CNNM1 overexpression in C18-4 spermatogonial cell lines upregulated genes involved in cell proliferation, nucleic acid metabolism, male germ cell development, and cell cycle regulation pathways, while CNNM1 knockdown altered cell cycle progression. GDNF-mediated self-renewal/proliferation enhanced CNNM1 expression, indicating CNNM1 participates in GDNF-driven SSC self-renewal signaling.\",\n      \"method\": \"Overexpression and knockdown in C18-4 cell line, proteome profiling, gene expression analysis, cell cycle analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, proteome profiling without deep mechanistic follow-up of individual pathway nodes\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"CNNM1 (ACDP1) is a transmembrane protein that forms part of high-molecular-weight complexes with the ion channel-kinase TRPM7 and ARL15 in native brain tissue; its cytoplasmic CBS-pair domain modulates TRPM7 channel activity while its CNBH domain enhances TRPM7 kinase activity in vitro, and ARL15-mediated N-glycosylation of CNNMs (including CNNM1) negatively regulates Mg2+ transport; additionally, CNNM1 binds copper with high affinity in the cytoplasm and functions as a copper storage/chaperone protein, and in spermatogonial cells it regulates cell cycle progression and is associated with stem cell self-renewal downstream of GDNF signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CNNM1 (ACDP1) is a cytoplasmic-domain-bearing transmembrane protein of the CNNM/ACDP family that participates in divalent-cation homeostasis and signaling, with tissue expression restricted to brain and testis [#2]. In native rodent brain, CNNM1 is a stable component of high-molecular-weight complexes assembled with the ion channel-kinase TRPM7 and the small GTPase ARL15 [#4]. Within these complexes the CNNM cytoplasmic modules act through distinct surfaces: the CBS-pair domain modulates TRPM7 channel activity and is required for ARL15-mediated suppression of that channel, while the CNBH domain binds the TRPM7 kinase domain and enhances its catalytic activity in vitro [#6]. ARL15 binds the CNNM carboxy-terminal CBS domains and drives complex N-glycosylation of CNNMs, which negatively regulates Mg2+ transport [#5]. Independently of its channel-associated role, CNNM1 binds copper with high (nanomolar) affinity in the cytoplasm and alters cellular copper retention, consistent with a copper storage/chaperone function [#0]. In spermatogonial cells CNNM1 marks early c-KIT-/OCT3/4-positive cells and regulates cell-cycle progression, linking it to stem-cell self-renewal [#3]. Evidence from invertebrate orthologs places CNNM-mediated Mg2+ efflux upstream of AMPK-TORC1 and TORC2 signaling [#7, #8], but the membrane-transport activity of human CNNM1 itself has not been directly demonstrated in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established the basic expression and subcellular distribution of the then-uncharacterized ACDP1 protein, defining where it might act.\",\n      \"evidence\": \"Immunofluorescence of permeabilized HeLa cells and tissue expression survey\",\n      \"pmids\": [\"12657465\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single immunofluorescence experiment with no functional readout\", \"Nuclear localization conflicts with later plasma-membrane findings\", \"No mechanism linked to the protein\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Proposed an ion-transport role by linking ACDP/CNNM to the bacterial Mg2+/Co2+ efflux protein CorC and placing the mouse ortholog at the neuronal plasma membrane.\",\n      \"evidence\": \"Immunostaining of hippocampal neurons and sequence homology analysis\",\n      \"pmids\": [\"14723793\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Homology inference, not direct transport assay for CNNM1\", \"Localization conflicts with prior nuclear report\", \"No functional validation of transport\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Used a yeast family member to position CNNM-type proteins as a distinct branch of metal homeostasis acting independently of canonical metal transporters.\",\n      \"evidence\": \"Yeast MAM3 deletion, metal-tolerance assays, and epistasis with known transporters\",\n      \"pmids\": [\"15498024\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Yeast ortholog, not mammalian CNNM1\", \"Vacuolar localization may not map to human biology\", \"Metal specificity for CNNM1 unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed that CNNM1 has a metal-binding biochemical activity distinct from cation efflux, identifying high-affinity copper binding and a copper-retention effect.\",\n      \"evidence\": \"Immobilized metal affinity chromatography, isothermal titration calorimetry, and cellular copper-retention assays\",\n      \"pmids\": [\"17608643\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Relationship between copper binding and Mg2+ biology unresolved\", \"No structure of the copper-binding site\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected CNNM1 to a cellular phenotype, showing it regulates spermatogonial cell-cycle progression and associates with stemness downstream of differentiation cues.\",\n      \"evidence\": \"siRNA knockdown in GC1-spg cells with flow-cytometry cell-cycle analysis, IHC, and RT-PCR in mouse testis\",\n      \"pmids\": [\"27251091\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between CNNM1 ion/copper activity and cell cycle not defined\", \"Single lab\", \"No in vivo loss-of-function\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated, via invertebrate genetics, that CNNM-mediated Mg2+ efflux acts upstream of AMPK-TORC1 signaling to control development.\",\n      \"evidence\": \"C. elegans cnnm-1/cnnm-3 mutant analysis, Mg2+ supplementation rescue, and aak-2 epistasis\",\n      \"pmids\": [\"27564576\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ortholog, not human CNNM1\", \"Direct efflux activity of CNNM1 not measured\", \"Phenotype reflects combined cnnm-1/cnnm-3 loss\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified CNNM1 as a native partner of TRPM7 and ARL15 in brain, establishing a physiological ternary complex that controls channel activity.\",\n      \"evidence\": \"Multi-epitope affinity purification and quantitative MS from rodent brain plus heterologous reconstitution and electrophysiology\",\n      \"pmids\": [\"34766907\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CNNM1-specific contribution versus CNNM2-4 not separated\", \"Stoichiometry and structure of the complex undefined\", \"Functional consequence in neurons not shown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined ARL15 as a CBS-domain-binding regulator that controls CNNM N-glycosylation and thereby Mg2+ transport.\",\n      \"evidence\": \"Co-immunoprecipitation, in silico modeling, immunocytochemistry, siRNA knockdown, and 25Mg2+ uptake assays\",\n      \"pmids\": [\"34089346\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CNNM1-specific Mg2+ transport not isolated\", \"Glycosylation site mapping incomplete\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the CNNM-Mg2+-mTOR axis to TORC2, showing excess Mg2+ from CNNM loss suppresses TORC2 and alters body size and dauer formation.\",\n      \"evidence\": \"C. elegans mutant and RNAi epistasis through gtl-1 and TORC2 components with dauer assays\",\n      \"pmids\": [\"38373693\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ortholog system\", \"Effect attributed to Mg2+ accumulation rather than direct CNNM signaling\", \"Human relevance not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Dissected the domain logic of CNNM-TRPM7 coupling, separating complex assembly, channel modulation, and kinase enhancement onto distinct CNNM modules.\",\n      \"evidence\": \"Electrophysiology, in vitro kinase assays, binding assays, and domain truncation/mutagenesis\",\n      \"pmids\": [\"40962059\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mapping performed largely on CNNM2; CNNM1-specific behavior inferred\", \"In vitro kinase enhancement is modest and not validated in cells\", \"No structure of the assembled complex\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed CNNM1 within GDNF-driven spermatogonial stem-cell self-renewal, linking its expression to proliferation and germ-cell development programs.\",\n      \"evidence\": \"Overexpression/knockdown in C18-4 cells with proteome profiling and cell-cycle analysis (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint, single lab\", \"Proteome correlations without mechanistic node validation\", \"No direct link to CNNM1 ion/copper activity\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether human CNNM1 itself directly transports Mg2+ (or another divalent cation) across membranes, and how its copper-binding, channel-modulating, and cell-cycle roles are mechanistically integrated, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct transport assay for human CNNM1\", \"No structure of CNNM1 alone or in the TRPM7/ARL15 complex\", \"Copper-chaperone and Mg2+/TRPM7 functions not reconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 5, 6]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\"TRPM7-CNNM-ARL15 complex\"],\n    \"partners\": [\"TRPM7\", \"ARL15\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}