CNNM2 is a multipass membrane protein that controls cellular and systemic magnesium balance. It is present at basolateral membranes of renal tubules, where its dysfunction causes renal magnesium wasting, and is also expressed in the nervous system. CNNM2 supports magnesium export and interacts with the TRPM7 channel to regulate divalent-cation entry. Its cytoplasmic tandem CBS domain binds Mg–ATP and regulatory partners including ARL15 and PRL phosphatases; these interactions link magnesium handling to changes in protein conformation and channel activity. The mechanism of autonomous human magnesium translocation remains unresolved. Pathogenic variants can cause hypomagnesemia with seizures and neurodevelopmental impairment.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005524 ATP binding | IEA GO_REF:0000107 | ACCEPT | Summary: CNNM2 directly binds ATP through its tandem CBS domain. Reason: The mouse donor has a genuine ATP-binding IDA premise. Independently, purified human CNNM2 residues 429–584 bind adenine nucleotides in NMR and crystal experiments, with magnesium favoring ATP binding and associated conformational changes. This supports ATP recognition, not ATP hydrolysis or a demonstrated ATP-driven pump. The intact tandem-domain result is not generalized to the 552-residue alternative product. Supporting Evidence: GO_REF:0000107 PMID:25184538 ATP binding is clearly favoured in the presence of Mg2+ file:human/CNNM2/CNNM2-source-evidence.json |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: CNNM2 acts at the plasma membrane in magnesium handling. Reason: Human kidney immunostaining places endogenous CNNM2 at basolateral tubular membranes, while controlled expression studies show cell-surface CNNM2. These target observations corroborate the conserved PAINT compartment across the mapped family sources. The target and donor observations support the compartment, while the historical IBD placement remains unreconstructed. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000248898 UNRESOLVED Human renal membrane staining and current experimental donor locations corroborate plasma-membrane activity; the historical ancestral placement was not reconstructed. Supporting Evidence: GO_REF:0000033 file:human/CNNM2/CNNM2-source-evidence.json |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic plasma-membrane mapping is supported. Reason: The UniProt location and mouse ortholog transfer agree with human renal membrane staining and cellular surface-expression experiments. Intracellular pools reported in some expression systems do not contradict the positive plasma-membrane localization or establish a single exclusive compartment. Supporting Evidence: GO_REF:0000120 file:human/CNNM2/CNNM2-source-evidence.json |
| GO:0010960 magnesium ion homeostasis | IBA GO_REF:0000033 | ACCEPT | Summary: Magnesium homeostasis is a conserved and experimentally grounded CNNM2 role. Reason: Human renal magnesium wasting segregates with CNNM2 variants, and cellular magnesium assays and zebrafish loss/rescue experiments support the target role. Current mouse, worm and zebrafish donor records provide genuine experimental premises for family homeostasis; the historical PAINT placement remains unreconstructed. Retention does not depend on donor count or imply a unique molecular transport mechanism. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN008532859 UNRESOLVED Human magnesium homeostasis and genuine family perturbation evidence corroborate this process, without resolving the historical ancestral placement. Supporting Evidence: GO_REF:0000033 file:human/CNNM2/CNNM2-source-evidence.json |
| GO:0010960 magnesium ion homeostasis | IEA GO_REF:0000002 | ACCEPT | Summary: The InterPro family mapping agrees with CNNM2 magnesium homeostasis. Reason: The official target entry contains IPR045095. Patient segregation, renal magnesium loss and controlled cellular magnesium measurements independently support the mapped process. The process is retained without assigning every neurodevelopmental consequence as a separate direct CNNM2 activity. Supporting Evidence: GO_REF:0000002 file:human/CNNM2/CNNM2-source-evidence.json |
| GO:0010960 magnesium ion homeostasis | IMP PMID:21397062 CNNM2, encoding a basolateral protein required for renal Mg2... | ACCEPT | Summary: CNNM2 variants disrupt renal magnesium balance. Reason: The original study reports segregating variants in two families with hypomagnesemia and inappropriate urinary magnesium loss. Its functional constructs are corrected full-length mouse Cnnm2, not human protein merely because HEK293 cells were used. Those recordings show magnesium-sensitive sodium currents rather than directly measured magnesium current; this limitation does not negate the human homeostasis phenotype. Supporting Evidence: |
| GO:0015095 magnesium ion transmembrane transporter activity | IBA GO_REF:0000033 | ACCEPT | Summary: Retain the inherited broad magnesium-transporter activity with mechanistic limits. Reason: Positive mouse CNNM2-dependent efflux, magnesium lowering in TRPM7-knockout cells, and the original oocyte currents support retaining the broad transport inference. Human isoform 1 also has positive bacterial complementation and uptake evidence, whereas a later controlled human HEK293 study found no increased currents, influx or efflux. The positive export experiments support the broad inference, while autonomous human permeation, sodium coupling and activity across all natural products remain unresolved. TRPM7 regulation supplies separate evidence for channel regulation. The mouse donor is authenticated and has an IDA efflux premise; the historical PTN002635793 placement is not independently reconstructed. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002635793 UNRESOLVED The mouse donor has positive CNNM2 efflux evidence, balanced against context-dependent negative human assays. The historical IBD placement itself was not reconstructed. Supporting Evidence: GO_REF:0000033 file:human/CNNM2/CNNM2-source-evidence.json |
| GO:0015095 magnesium ion transmembrane transporter activity | IEA GO_REF:0000107 | ACCEPT | Summary: The mouse ortholog transfer has a positive CNNM2-specific export premise. Reason: The exact Q3TWN3 donor carries IDA from PMID:24706765, whose mouse constructs show magnesium efflux and loss of this response after CBS deletion or T568I substitution. Later experiments retain magnesium-lowering activity without TRPM7. Contradictory human HEK293 results are acknowledged, so the broad inference is retained without claiming universally autonomous human transport or a proven sodium/magnesium exchange stoichiometry. Supporting Evidence: GO_REF:0000107 PMID:24706765 Almost no Mg 2+ efflux was observed file:human/CNNM2/CNNM2-source-evidence.json |
| GO:0016323 basolateral plasma membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Basolateral renal localization is supported independently of the ortholog transfer. Reason: The current mouse donor includes genuine localization records from PMID:21397062. That same source directly stains human kidney CNNM2 at basolateral membranes in the thick ascending limb and distal convoluted tubule. Preserve the electronic source while grounding the compartment in the independently inspected human tissue result. |
| GO:0016323 basolateral plasma membrane | IMP PMID:21397062 CNNM2, encoding a basolateral protein required for renal Mg2... | ACCEPT | Summary: Human kidney CNNM2 localizes to basolateral tubular membranes. Reason: The original human kidney immunohistochemistry, with segment markers and antibody controls, supports the compartment. Mouse localization and MDCK expression are separate corroborating experiments; mutant current phenotypes do not change the original IMP code or establish the location of every alternative human product. Supporting Evidence: |
| GO:0045202 synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The mouse donor has a positive synaptic localization observation. Reason: The exact SynGO record 5563 describes antibody staining of endogenous Cnnm2 in cultured mouse hippocampal neurons, partially overlapping SYP and PSD95. This supports contextual synaptic localization by orthology but does not resolve pre- versus postsynaptic placement or establish a synapse-specific molecular function. The record states that PMID:31171447 is an interim resource citation pending the experiment publication; the inspected localization evidence is the actual curator rationale and target row, distinct from the resource paper. Supporting Evidence: GO_REF:0000107 file:human/CNNM2/CNNM2-source-evidence.json |
| GO:0098978 glutamatergic synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The glutamatergic-synapse transfer is retained as contextual localization. Reason: The same authenticated mouse SynGO observation carries a glutamatergic-synapse extension and is represented in the current donor GOA. Its cultured-neuron colocalization supports this non-core compartment, with no resolution of pre- versus postsynaptic protein placement or direct endogenous human assay. The resource-paper citation remains explicitly distinct from the later target-specific curator evidence. Supporting Evidence: GO_REF:0000107 file:human/CNNM2/CNNM2-source-evidence.json |
| GO:1903830 magnesium ion transmembrane transport | IEA GO_REF:0000108 | ACCEPT | Summary: CNNM2 participates in magnesium movement across cell membranes. Reason: CNNM2-dependent cellular magnesium efflux and uptake experiments support membrane transport participation, including a separable TRPM7-dependent influx-regulatory role. The source is the existing transporter-to-process mapping. Retain the process without claiming that every measured flux traverses CNNM2 itself or specifying an unproven coupling reaction. |
| GO:0099106 ion channel regulator activity | ISS PMID:40962059 The cytoplasmic domains of the CNNM family of transmembrane ... | NEW | Summary: CNNM2 directly associates with and regulates the TRPM7 channel. Reason: Mouse CNNM2 coimmunoprecipitates with TRPM7 and enhances divalent-cation entry that requires the TRPM7 pore. The later study maps physical interactions and shows current rescue by the explicitly export-disabled S269P and CBS-deletion constructs, with CNBH and ARL15-binding requirements. Together these support a conserved channel-regulatory MF distinct from CNNM2 transport. This is an ortholog inference, not a human IDA or a claim that all natural products were tested; the precise gating mechanism remains unresolved. Supporting Evidence: PMID:34928937 TRPM7’s pore is required for CNNM2 stimulation file:human/CNNM2/CNNM2-source-evidence.json |
Loading supporting content…
Download this section (compressed HTML)Q: Which physiological partners and membrane conditions account for positive CNNM2-dependent magnesium export versus negative human isoform transport assays, and does purified human CNNM2 itself translocate magnesium?
Q: How do the 875-, 853- and 552-residue human products differ in surface delivery, Mg–ATP recognition and TRPM7 regulation?
Q: Does endogenous CNNM2 regulate TRPM7 gating, the fraction of functional channels, or another step in native renal and neuronal cells?
Experiment: Compare sequence-verified human products in matched cellular flux assays and purified membrane reconstitution, separating CNNM2-mediated export from TRPM7-dependent entry with pore-disabled and binding-defective controls.
Experiment: Use endogenous tagging and validated antibodies to resolve CNNM2 localization and channel regulation in renal epithelia and excitatory synapses, distinguishing pre- and postsynaptic compartments.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)