CNNM4 is a plasma-membrane magnesium transporter with an extracellular domain, a transmembrane transport region, tandem CBS domains and a cyclic nucleotide-binding homology domain. It couples magnesium export to sodium entry and also associates with TRPM7 to promote divalent-cation channel activity. MgATP binding organizes its cytoplasmic domains, and full-length human CNNM4 forms an asymmetric dimer-of-dimers assembly. Basolateral epithelial localization supports directional magnesium movement and systemic magnesium balance. Biallelic pathogenic variants cause Jalili syndrome, combining cone-rod dystrophy with defective enamel formation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:15840172 Physical interaction and functional coupling between ACDP4 a... | KEEP AS NON CORE | Summary: CNNM4 binds RBM4B, called RBM30 in the original study. Reason: The human brain-library screen initially yielded a clone containing COX11 and RBM30 plasmids. The investigators subsequently retested the two prey proteins separately with full-length ACDP4 and negative-vector controls, supporting each positive interaction. RBM4B is an RNA-binding protein, but no verified more specific partner-class term captures this pair. The assay does not establish a physiological RNA-regulatory role for CNNM4. Supporting Evidence: PMID:15840172 ACDP4 also interacts with RBM30 |
| GO:0005515 protein binding | IPI PMID:15840172 Physical interaction and functional coupling between ACDP4 a... | KEEP AS NON CORE | Summary: CNNM4 has an experimentally supported interaction with COX11. Reason: Separate yeast two-hybrid retesting supports the COX11 pair, and coexpression modifies metal-induced toxicity in HEK293 cells. COX11 is a copper-delivery assembly factor, so protein-folding chaperone binding would misclassify the partner. The proposed direct metal handoff and native complex architecture were not demonstrated. Supporting Evidence: PMID:15840172 ACDP4 physically interacts with COX11 |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Plasma-membrane activity is supported by target experiments and family evidence. Reason: The exact donor identities and current same-term records support the inherited cellular location. Independent human CNNM4 expression, surface labeling and transport measurements establish activity at the plasma membrane. The target appearing among PAINT sources is legitimate experimental grounding, while the historical ancestral placement has not been reconstructed. The short alternative product is not covered by the full-length experiments. Propagation Review Root cause: NO FAILURE CORE Sources checked: FB:FBgn0262124 SUPPORTS TRANSFER Official identity resolves to Drosophila uex. Current same-term records provide positive experimental or curator-stated grounding, whose exact evidence and reference identifiers are retained in the source index. This assesses current source support, not the uninspected historical ancestral placement. MGI:MGI:1891366 SUPPORTS TRANSFER Official identity resolves to mouse Cnnm1. Current same-term records provide positive experimental or curator-stated grounding, whose exact evidence and reference identifiers are retained in the source index. This assesses current source support, not the uninspected historical ancestral placement. MGI:MGI:2151054 SUPPORTS TRANSFER Official identity resolves to mouse Cnnm2. Current same-term records provide positive experimental or curator-stated grounding, whose exact evidence and reference identifiers are retained in the source index. This assesses current source support, not the uninspected historical ancestral placement. MGI:MGI:2151060 UNRESOLVED Official identity resolves to mouse Cnnm4. The inspected same-term records are propagated; their original experimental chain is not resolved by this lookup. The target is independently supported, and the source is not rejected or called circular. PANTHER:PTN000248898 UNRESOLVED The current official annotation query confirms this node identifier in propagated records. Historical PAINT tree, alignment and IBD placement were not independently reconstructed; no failure is inferred from donor count. UniProtKB:Q6P4Q7 SUPPORTS TRANSFER The target has a current HPA IDA plasma-membrane record, qualified by uncertain antibody reliability, and independent direct membrane evidence. Its use as a PAINT descendant source is expected and is not circular. Historical node placement remains uninspected. UniProtKB:Q9H8M5 UNRESOLVED Official identity resolves to human CNNM2. The inspected same-term records are propagated; their original experimental chain is not resolved by this lookup. The target is independently supported, and the source is not rejected or called circular. WB:WBGene00016343 UNRESOLVED Official identity resolves to worm cnnm-3. The inspected same-term records are propagated; their original experimental chain is not resolved by this lookup. The target is independently supported, and the source is not rejected or called circular. WB:WBGene00016879 UNRESOLVED Official identity resolves to worm cnnm-1. The inspected same-term records are propagated; their original experimental chain is not resolved by this lookup. The target is independently supported, and the source is not rejected or called circular. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: Human CNNM4 has a supported plasma-membrane location. Reason: The current HPA record reports plasma-membrane staining in A-431, U-251MG and U2OS cells, with an uncertain reliability rating and additional actin-filament staining. Independent sequence-verified human CNNM4 localization and surface-labeling experiments corroborate the membrane location; the HPA rating is not converted into a new actin-function claim. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: The UniProt plasma-membrane mapping is consistent with direct evidence. Reason: SL-0039 maps the recorded plasma-membrane location. Human CNNM4 membrane topology, surface expression and cellular transport independently support this broad location; polarized epithelial basolateral localization is a context-specific refinement rather than a universal exclusion of other membrane regions. |
| GO:0010960 magnesium ion homeostasis | IBA GO_REF:0000033 | ACCEPT | Summary: CNNM4 performs work that maintains magnesium balance. Reason: Human CNNM4 mediates magnesium export and regulates TRPM7-dependent influx. Mouse Cnnm4 loss causes reduced serum magnesium and intestinal malabsorption. The mapped donor records include positive experimental magnesium-homeostasis annotations; their animal and cellular contexts are kept distinct from historical PAINT node placement. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:2151060 SUPPORTS TRANSFER Official identity resolves to mouse Cnnm4. Current same-term records provide positive experimental or curator-stated grounding, whose exact evidence and reference identifiers are retained in the source index. This assesses current source support, not the uninspected historical ancestral placement. PANTHER:PTN008532859 UNRESOLVED The current official annotation query confirms this node identifier in propagated records. Historical PAINT tree, alignment and IBD placement were not independently reconstructed; no failure is inferred from donor count. UniProtKB:Q9H8M5 SUPPORTS TRANSFER Official identity resolves to human CNNM2. Current same-term records provide positive experimental or curator-stated grounding, whose exact evidence and reference identifiers are retained in the source index. This assesses current source support, not the uninspected historical ancestral placement. WB:WBGene00016343 SUPPORTS TRANSFER Official identity resolves to worm cnnm-3. Current same-term records provide positive experimental or curator-stated grounding, whose exact evidence and reference identifiers are retained in the source index. This assesses current source support, not the uninspected historical ancestral placement. WB:WBGene00016879 SUPPORTS TRANSFER Official identity resolves to worm cnnm-1. Current same-term records provide positive experimental or curator-stated grounding, whose exact evidence and reference identifiers are retained in the source index. This assesses current source support, not the uninspected historical ancestral placement. ZFIN:ZDB-GENE-050208-36 SUPPORTS TRANSFER Official identity resolves to zebrafish cnnm2a. Current same-term records provide positive experimental or curator-stated grounding, whose exact evidence and reference identifiers are retained in the source index. This assesses current source support, not the uninspected historical ancestral placement. ZFIN:ZDB-GENE-090311-26 SUPPORTS TRANSFER Official identity resolves to zebrafish cnnm2b. Current same-term records provide positive experimental or curator-stated grounding, whose exact evidence and reference identifiers are retained in the source index. This assesses current source support, not the uninspected historical ancestral placement. |
| GO:0010960 magnesium ion homeostasis | IEA GO_REF:0000002 | ACCEPT | Summary: The CNNM-family homeostasis mapping agrees with the target mechanism. Reason: The actual IPR045095 record maps to magnesium ion homeostasis. Direct human CNNM4 transport and mouse physiological evidence establish this role independently of the family mapping. Family membership alone is not used to assign a particular transport mechanism to every CNNM paralog. |
| GO:0015081 sodium ion transmembrane transporter activity | IBA GO_REF:0000033 | MODIFY | Summary: The coupled magnesium:sodium antiporter term captures the measured activity. Reason: The sodium-transporter assertion has positive experimental grounding, and human CNNM4 assays permit a more precise coupled classification. Sodium removal blocks magnesium efflux, sodium restoration restores it, and SBFI/Mag-fura2 measurements show sodium entry alongside magnesium loss. The reported approximately 2:1 cellular flux relationship is consistent with electroneutral exchange; it is not a purified single-cycle stoichiometry. Full-length human structures and surface-controlled mutagenesis strengthen target attribution. The original propagation source remains intact; this refinement does not assert an error in historical PAINT placement. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: MGI:MGI:2151060 SUPPORTS TRANSFER Official identity resolves to mouse Cnnm4. Current same-term records provide positive experimental or curator-stated grounding, whose exact evidence and reference identifiers are retained in the source index. This assesses current source support, not the uninspected historical ancestral placement. The original publication combines mouse in vivo work with explicitly human CNNM4 transport constructs; the direct human evidence independently supports this target refinement. PANTHER:PTN002635769 UNRESOLVED The current official annotation query confirms this node identifier in propagated records. Historical PAINT tree, alignment and IBD placement were not independently reconstructed; no failure is inferred from donor count. Proposed replacements: magnesium:sodium antiporter activity Supporting Evidence: GO_REF:0000033 PMID:24339795 In the absence of extracellular Na+, Mg2+ depletion did not induce Mg2+ extrusion |
| GO:0015081 sodium ion transmembrane transporter activity | IEA GO_REF:0000107 | MODIFY | Summary: The coupled magnesium:sodium antiporter term captures the measured activity. Reason: The sodium-transporter assertion has positive experimental grounding, and human CNNM4 assays permit a more precise coupled classification. Sodium removal blocks magnesium efflux, sodium restoration restores it, and SBFI/Mag-fura2 measurements show sodium entry alongside magnesium loss. The reported approximately 2:1 cellular flux relationship is consistent with electroneutral exchange; it is not a purified single-cycle stoichiometry. Full-length human structures and surface-controlled mutagenesis strengthen target attribution. The original Ensembl Compara ortholog-transfer source remains intact. The refinement uses direct human CNNM4 evidence while retaining the mouse Cnnm4 donor attribution; it does not assert a defect in the orthology transfer. Proposed replacements: magnesium:sodium antiporter activity |
| GO:0015095 magnesium ion transmembrane transporter activity | IBA GO_REF:0000033 | MODIFY | Summary: The coupled magnesium:sodium antiporter term captures the measured activity. Reason: The magnesium-transporter assertion has positive experimental grounding, and human CNNM4 assays permit a more precise coupled classification. Sodium removal blocks magnesium efflux, sodium restoration restores it, and SBFI/Mag-fura2 measurements show sodium entry alongside magnesium loss. The reported approximately 2:1 cellular flux relationship is consistent with electroneutral exchange; it is not a purified single-cycle stoichiometry. Full-length human structures and surface-controlled mutagenesis strengthen target attribution. The original propagation source remains intact; this refinement does not assert an error in historical PAINT placement. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: MGI:MGI:2151060 SUPPORTS TRANSFER Official identity resolves to mouse Cnnm4. Current same-term records provide positive experimental or curator-stated grounding, whose exact evidence and reference identifiers are retained in the source index. This assesses current source support, not the uninspected historical ancestral placement. The original publication combines mouse in vivo work with explicitly human CNNM4 transport constructs; the direct human evidence independently supports this target refinement. PANTHER:PTN002635769 UNRESOLVED The current official annotation query confirms this node identifier in propagated records. Historical PAINT tree, alignment and IBD placement were not independently reconstructed; no failure is inferred from donor count. Proposed replacements: magnesium:sodium antiporter activity |
| GO:0015095 magnesium ion transmembrane transporter activity | IEA GO_REF:0000107 | MODIFY | Summary: The coupled magnesium:sodium antiporter term captures the measured activity. Reason: The magnesium-transporter assertion has positive experimental grounding, and human CNNM4 assays permit a more precise coupled classification. Sodium removal blocks magnesium efflux, sodium restoration restores it, and SBFI/Mag-fura2 measurements show sodium entry alongside magnesium loss. The reported approximately 2:1 cellular flux relationship is consistent with electroneutral exchange; it is not a purified single-cycle stoichiometry. Full-length human structures and surface-controlled mutagenesis strengthen target attribution. The original Ensembl Compara ortholog-transfer source remains intact. The refinement uses direct human CNNM4 evidence while retaining the mouse Cnnm4 donor attribution; it does not assert a defect in the orthology transfer. Proposed replacements: magnesium:sodium antiporter activity |
| GO:0015693 magnesium ion transport | IBA GO_REF:0000033 | ACCEPT | Summary: CNNM4 directly contributes to magnesium transport. Reason: The broad inherited process remains correct: human CNNM4 supports magnesium movement across the plasma membrane, with mouse intestinal physiology providing complementary in vivo evidence. The already-present transmembrane-transport assertion supplies route specificity, so no additional process assertion is needed. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:2151060 SUPPORTS TRANSFER Official identity resolves to mouse Cnnm4. Current same-term records provide positive experimental or curator-stated grounding, whose exact evidence and reference identifiers are retained in the source index. This assesses current source support, not the uninspected historical ancestral placement. The original publication combines mouse in vivo work with explicitly human CNNM4 transport constructs; the direct human evidence independently supports retention of the target magnesium-transport assertion. PANTHER:PTN002635769 UNRESOLVED The current official annotation query confirms this node identifier in propagated records. Historical PAINT tree, alignment and IBD placement were not independently reconstructed; no failure is inferred from donor count. |
| GO:0016323 basolateral plasma membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Basolateral membrane localization is supported in polarized epithelia. Reason: The exact mouse ortholog has basolateral localization records. The cited study also uses human CNNM4-FLAG in polarized MDCK cells and detects it with the basolateral Na/K-ATPase marker below ZO-1. Endogenous mouse intestinal and ameloblast localization corroborates this context; CNNM4 is not claimed to be exclusively basolateral in every cell. |
| GO:0030003 intracellular monoatomic cation homeostasis | IDA PMID:15840172 Physical interaction and functional coupling between ACDP4 a... | KEEP AS NON CORE | Summary: The original study supports a broad metal-homeostasis context with assay limits. Reason: ACDP4 expression altered copper-, manganese- and cobalt-induced cell toxicity, and COX11 coexpression enhanced these effects. The authors explicitly called for direct metal-accumulation measurements; viability alone does not identify a transported metal or flux direction. Later direct magnesium measurements support CNNM4 cation homeostasis, while the original broad assertion is retained as contextual evidence. |
| GO:0032991 protein-containing complex | IDA PMID:15840172 Physical interaction and functional coupling between ACDP4 a... | KEEP AS NON CORE | Summary: CNNM4 participates in protein assemblies, with the original interaction context preserved. Reason: The original COX11/RBM30 study supports physical association through two-hybrid experiments but leaves native architecture and metal handoff unresolved. Independent human CNNM4 cryo-EM directly demonstrates an MgATP-bound tetramer, and TRPM7 coimmunoprecipitation establishes another assembly context. These observations support the broad complex term without treating the original pair as a resolved native complex. |
| GO:0035725 sodium ion transmembrane transport | IEA GO_REF:0000108 | ACCEPT | Summary: Sodium movement is part of CNNM4-mediated exchange. Reason: The logical inference from sodium-transporter activity is independently supported by human CNNM4 SBFI sodium measurements coupled to magnesium efflux. Sodium entry is the counter-ion component of exchange, not merely a downstream consequence of TRPM7 regulation. |
| GO:1903830 magnesium ion transmembrane transport | IEA GO_REF:0000108 | ACCEPT | Summary: CNNM4 mediates magnesium transmembrane transport. Reason: The inference from magnesium-transporter activity agrees with human cellular efflux, sodium-dependence experiments and full-length structural/mutational evidence. It refers to the transport performed by CNNM4; TRPM7-dependent influx is described separately as channel regulation. |
| GO:0099106 ion channel regulator activity | IDA PMID:34928937 CNNM proteins selectively bind to the TRPM7 channel to stimu... | NEW | Summary: Human CNNM4 interacts with TRPM7 and promotes its channel activity. Reason: CNNM4 coimmunoprecipitates with TRPM7, including endogenous proteins, and modest WT human CNNM4 reexpression restores TRPM7 whole-cell currents and magnesium uptake in CNNM3/4-deficient cells. Similar surface-channel levels and the SLC41A1 comparator distinguish this from generic magnesium lowering. Human CNNM4 S196P and CBS-deletion variants retain current rescue despite impaired efflux. This is performed channel regulation, not assignment of the TRPM7 pore or kinase activity to CNNM4. The new MF has no typed ancestor/descendant overlap with the seeded terms or ATP-binding addition. |
| GO:0005524 ATP binding | IDA PMID:24706765 Mg2+-dependent interactions of ATP with the cystathionine-Ξ²-... | NEW | Summary: Human CNNM4 directly binds MgATP through its CBS region. Reason: Purified human CNNM4 residues 359β511 bind radiolabeled ATP in a magnesium-dependent filter-binding assay with a GST control; the reported affinity is 43.4 Β± 8.9 Β΅M. Full-length human CNNM4 also contains bound MgATP in the cryo-EM structure. This is measured recognition rather than an inference from a domain name, and it does not establish ATP hydrolysis. The 263-residue alternative product lacks the assayed CBS segment. ATP binding is nonredundant with the transport and channel-regulator MFs. Supporting Evidence: PMID:24706765 all of these proteins, except for CNNM3, showed saturable binding with ATP |
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Download this section (compressed HTML)Q: What is the complete human CNNM4 ion-coupling cycle, including the inward-facing state and the identity and occupancy of the putative sodium sites?
Q: Does the 263-residue Q6P4Q7-2 product have a stable physiological role despite lacking the transmembrane and CBS regions?
Q: How are CNNM4 efflux and TRPM7 regulation coordinated in polarized epithelia and in retinal or enamel-forming cells?
Experiment: Reconstitute purified full-length human CNNM4 into oriented proteoliposomes and measure simultaneous sodium and magnesium flux under controlled gradients, with empty-vesicle and transport-site mutant controls.
Hypothesis: CNNM4 directly catalyzes coupled sodium/magnesium exchange with an experimentally measurable coupling relationship.
Experiment: Compare matched full-length CNNM4 and the reconstructed short alternative product for expression, localization, magnesium efflux and TRPM7 current rescue at comparable abundance.
Hypothesis: Loss of the transmembrane and CBS regions separates the short product from the established full-length transport mechanism.
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