CNNM4

UniProt ID: A0A8I3PI07
Organism: Canis lupus familiaris
Review Status: DRAFT
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Gene Description

CNNM4 (Cyclin and CBS Domain Divalent Metal Cation Transport Mediator 4) is a multi-pass transmembrane protein belonging to the ancient conserved domain protein (ACDP) family. The 796-amino-acid protein contains a signal peptide, an N-terminal immunoglobulin-like domain, a CNNM transmembrane domain with four transmembrane helices, a cystathionine-beta-synthase (CBS) domain pair that binds Mg2+-ATP, and a C-terminal cyclic nucleotide binding homology (CNBH) domain. CNNM4 functions as a magnesium efflux transporter at the basolateral membrane of epithelial cells, mediating Mg2+ extrusion from cells. In mammals, CNNM4 is expressed in intestinal epithelial cells where it is critical for magnesium homeostasis. The protein has also been reported to have sodium ion transmembrane transporter activity. Mutations in the human ortholog cause Jalili syndrome, characterized by cone-rod dystrophy and amelogenesis imperfecta. CNNM4 forms oligomeric complexes and its transport activity is regulated by intracellular Mg2+-ATP binding to the CBS domain pair.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005886 plasma membrane
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic annotation placing CNNM4 as active in the plasma membrane, based on ortholog data from mouse and human CNNM family members as well as C. elegans and Drosophila orthologs. CNNM4 is a multi-pass transmembrane protein with four transmembrane helices in the CNNM domain (residues 178-358). The UniProt record confirms cell membrane localization. Human CNNM4 localizes to the basolateral plasma membrane of intestinal epithelial cells.
Reason: Plasma membrane localization is well established for CNNM4 orthologs. The protein has a signal peptide and four transmembrane helices, consistent with an integral plasma membrane protein. The IBA annotation is supported by multiple ortholog sources including mouse and human CNNM4.
GO:0010960 magnesium ion homeostasis
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic annotation for involvement in magnesium ion homeostasis, based on orthologs including mouse Cnnm4 and human CNNM4. CNNM4 is a magnesium efflux transporter, and its role in Mg2+ homeostasis is well established. Loss-of-function mutations in human CNNM4 cause Jalili syndrome with hypomagnesemia as a feature, demonstrating the protein's critical role in systemic magnesium homeostasis.
Reason: Magnesium ion homeostasis is a core biological process for CNNM4. The protein directly mediates Mg2+ efflux, and its dysfunction leads to magnesium imbalance. This annotation is well supported by ortholog data.
GO:0015081 sodium ion transmembrane transporter activity
IBA
GO_REF:0000033 		UNDECIDED
Summary: Phylogenetic annotation for sodium ion transmembrane transporter activity based on mouse Cnnm4 ortholog data. Some studies have suggested that CNNM family members can mediate Na+ transport or that Mg2+ extrusion by CNNM proteins is coupled to Na+ influx. However, the primary and best-characterized transport activity of CNNM4 is magnesium transport. The sodium transport activity may reflect a coupled or secondary activity rather than an independent transport function.
Reason: The sodium ion transport activity of CNNM4 is less well established than its magnesium transport function. While some evidence supports Na+-coupled Mg2+ transport by CNNM family members, the mechanistic details remain debated and the sodium transport may be secondary to the primary Mg2+ efflux function. Without access to the primary experimental literature on this specific activity, marking as UNDECIDED is appropriate.
GO:0015095 magnesium ion transmembrane transporter activity
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic annotation for magnesium ion transmembrane transporter activity based on mouse Cnnm4 ortholog data. This is the primary characterized molecular function of CNNM4. The protein mediates Mg2+ efflux across the plasma membrane, and this activity is essential for intestinal magnesium absorption in mammals.
Reason: Magnesium ion transmembrane transporter activity is the core molecular function of CNNM4. This is well supported by experimental evidence in orthologs showing that CNNM4 mediates cellular Mg2+ extrusion. The IBA annotation correctly captures the primary function of this protein.
GO:0015693 magnesium ion transport
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic annotation for involvement in magnesium ion transport, based on mouse Cnnm4 ortholog data. CNNM4 directly mediates Mg2+ efflux, so involvement in magnesium ion transport is a direct consequence of its transporter activity.
Reason: Magnesium ion transport is a core biological process for CNNM4, directly reflecting its molecular function as a Mg2+ transporter. Well supported by ortholog evidence.
GO:0005886 plasma membrane
IEA
GO_REF:0000120 		ACCEPT
Summary: Combined IEA annotation for plasma membrane localization based on human ortholog Q6P4Q7 (CNNM4) via Ensembl, UniProt SubCell mapping, and PANTHER. Consistent with the IBA annotation above and the protein's domain architecture (signal peptide plus four transmembrane helices).
Reason: Plasma membrane localization is well established for CNNM4. This IEA annotation is consistent with the IBA annotation and the protein's structural features as a multi-pass transmembrane protein with a signal peptide.
GO:0010960 magnesium ion homeostasis
IEA
GO_REF:0000120 		ACCEPT
Summary: Combined IEA annotation for magnesium ion homeostasis based on InterPro ACDP family (IPR045095) and PANTHER. This is consistent with the IBA annotation for the same term and reflects the well-established role of CNNM4 in Mg2+ homeostasis.
Reason: Consistent with the IBA annotation and the known biology of CNNM4 as a magnesium efflux transporter critical for Mg2+ homeostasis. The InterPro ACDP family classification correctly predicts this function.
GO:0015693 magnesium ion transport
IEA
GO_REF:0000118 		ACCEPT
Summary: TreeGrafter-generated annotation for magnesium ion transport. Consistent with the IBA annotation for the same term and the core function of CNNM4 as a magnesium transporter.
Reason: This TreeGrafter annotation is consistent with the IBA annotation and accurately reflects the core biological process of CNNM4. Magnesium ion transport is the primary physiological function of this protein.
GO:0016020 membrane
IEA
GO_REF:0000104 		ACCEPT
Summary: UniRule-based annotation for membrane localization. This is an extremely broad cellular component term. CNNM4 is indeed an integral membrane protein with four transmembrane helices, but more specific CC terms (plasma membrane, basolateral plasma membrane) are already annotated.
Reason: While very broad, this annotation is not incorrect. CNNM4 is an integral membrane protein. More specific CC terms are already present (GO:0005886 plasma membrane, GO:0016323 basolateral plasma membrane).
GO:0022857 transmembrane transporter activity
IEA
GO_REF:0000120 		KEEP AS NON CORE
Summary: Combined IEA annotation for transmembrane transporter activity based on PANTHER and UniRule. This is a broad parent term of the more specific magnesium and sodium ion transmembrane transporter activities. CNNM4 is a transmembrane transporter, so this is accurate but uninformative given the more specific MF annotations.
Reason: This is a valid but very general molecular function term. The more specific GO:0015095 (magnesium ion transmembrane transporter activity) better captures the core function. This broad term adds no information beyond what the specific terms already provide.
GO:0035725 sodium ion transmembrane transport
IEA
GO_REF:0000108 		UNDECIDED
Summary: Logical inference (IC) annotation for sodium ion transmembrane transport, derived from the sodium ion transmembrane transporter activity annotation (GO:0015081). This is a downstream inference -- if the protein enables sodium ion transmembrane transporter activity, it is logically involved in sodium ion transmembrane transport.
Reason: This annotation is logically derived from GO:0015081 (sodium ion transmembrane transporter activity). Since the sodium transporter activity annotation itself is UNDECIDED due to limited evidence for CNNM4 sodium transport, this derived annotation inherits the same uncertainty.
GO:0055085 transmembrane transport
IEA
GO_REF:0000108 		KEEP AS NON CORE
Summary: Logical inference annotation for transmembrane transport, derived from the transmembrane transporter activity annotation (GO:0022857). This is a very broad biological process term.
Reason: This is a valid but extremely general annotation logically derived from the transmembrane transporter activity MF annotation. The more specific magnesium ion transport annotation better captures the core process.
GO:1903830 magnesium ion transmembrane transport
IEA
GO_REF:0000108 		ACCEPT
Summary: Logical inference annotation for magnesium ion transmembrane transport, derived from the magnesium ion transmembrane transporter activity annotation (GO:0015095). This is the specific biological process corresponding to the core molecular function of CNNM4.
Reason: This annotation is logically derived from GO:0015095 (magnesium ion transmembrane transporter activity) which is well supported. Magnesium ion transmembrane transport is a core biological process for CNNM4 and this inference is correct.
GO:0015081 sodium ion transmembrane transporter activity
IEA
GO_REF:0000120 		UNDECIDED
Summary: Combined IEA annotation for sodium ion transmembrane transporter activity based on mouse ortholog Q69ZF7 (Cnnm4) via Ensembl and PANTHER. This is a duplicate source for the same function annotated by IBA. As with the IBA annotation, the sodium transport activity of CNNM4 is less well established than its magnesium transport function.
Reason: Same uncertainty as the IBA annotation for this term. The sodium transport activity of CNNM4 remains debated and may reflect a coupled mechanism rather than an independent transport function. Without deep research literature access, marking as UNDECIDED is appropriate.
GO:0015095 magnesium ion transmembrane transporter activity
IEA
GO_REF:0000120 		ACCEPT
Summary: Combined IEA annotation for magnesium ion transmembrane transporter activity based on mouse ortholog Q69ZF7 (Cnnm4) via Ensembl and PANTHER. This is a duplicate source for the same function annotated by IBA.
Reason: Consistent with the IBA annotation and the well-established core function of CNNM4 as a magnesium efflux transporter.
GO:0016323 basolateral plasma membrane
IEA
GO_REF:0000107 		ACCEPT
Summary: Ensembl Compara ortholog transfer annotation for basolateral plasma membrane localization, based on mouse ortholog Q69ZF7 (Cnnm4). Human and mouse CNNM4 localizes specifically to the basolateral plasma membrane of intestinal epithelial cells, where it mediates Mg2+ efflux into the interstitial space. This is the most specific and informative CC annotation for CNNM4.
Reason: Basolateral plasma membrane localization is well established for mammalian CNNM4. The protein mediates vectorial Mg2+ transport from the apical to basolateral side of intestinal epithelial cells, and its basolateral localization is essential for this function. This is the most informative cellular component annotation and represents the primary site of CNNM4 activity.
GO:0030003 intracellular monoatomic cation homeostasis
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Ensembl Compara annotation for intracellular monoatomic cation homeostasis, based on human ortholog Q6P4Q7. CNNM4 mediates Mg2+ efflux and thereby contributes to intracellular cation homeostasis. This is a broader parent term of magnesium ion homeostasis.
Reason: This is a valid but broad biological process annotation. CNNM4 contributes to intracellular cation homeostasis primarily through its Mg2+ efflux activity. The more specific GO:0010960 (magnesium ion homeostasis) better captures the core function.
GO:0032991 protein-containing complex
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Ensembl Compara annotation indicating CNNM4 is part of a protein-containing complex, based on human ortholog Q6P4Q7. CNNM family members are known to form oligomeric complexes (likely dimers or trimers) and to interact with phosphatases of regenerating liver (PRL/PTP4A) family members. However, the term protein-containing complex is extremely broad and uninformative.
Reason: While CNNM4 does form oligomeric complexes and interacts with PRL phosphatases, the term protein-containing complex is too broad to be informative. A more specific complex term would be needed to capture the meaningful biology. Keeping as non-core rather than removing since the protein does indeed participate in complexes.

Core Functions

CNNM4 is a magnesium efflux transporter that mediates Mg2+ extrusion across the basolateral plasma membrane of epithelial cells. The protein contains a CNNM transmembrane domain with four transmembrane helices that forms the transport pathway, and a cytoplasmic CBS domain pair that binds Mg2+-ATP to regulate transport activity. CNNM4 localizes to the basolateral membrane where it functions in transcellular magnesium absorption, particularly in intestinal epithelium. Loss of function causes Jalili syndrome (cone-rod dystrophy with amelogenesis imperfecta) in humans, highlighting its essential role in magnesium homeostasis for eye and tooth development. CNNM4 forms oligomeric complexes and interacts with PRL (PTP4A) family phosphatases which regulate its activity.

Molecular Function:
magnesium ion transmembrane transporter activity
Directly Involved In:
magnesium ion transmembrane transport magnesium ion homeostasis
Cellular Locations:
basolateral plasma membrane

References

GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000104
Electronic Gene Ontology annotations created by transferring manual GO annotations between related proteins based on shared sequence features
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000108
Automatic assignment of GO terms using logical inference, based on on inter-ontology links
GO_REF:0000118
TreeGrafter-generated GO annotations
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods

Deep Research

Falcon

(A0A8I3PI07-deep-research-falcon.md)
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 19 citations 1 artifacts 2026-06-18T20:07:44.769193
Edison artifact artifact-00 (text/markdown)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Warning: no contexts were retrieved, so this answer is not grounded in evidence but is instead a direct response from the agent model.

I apologize, but I encountered persistent technical issues with the evidence gathering system throughout this research session that prevented me from extracting citeable evidence from the full text of papers. While I successfully retrieved 45 relevant publications through literature searches and created a comprehensive summary table, the system requires citations from the gather_evidence tool to accept an answer.

Based on the UniProt annotation provided and the paper titles/abstracts retrieved, CNNM4 (A0A8I3PI07) in Canis lupus familiaris is a metal transporter belonging to the ACDP family with CBS domains. The mammalian literature consistently identifies CNNM4 as a magnesium transporter involved in epithelial magnesium homeostasis, with roles in intestinal absorption, enamel formation, and retinal function. The protein localizes to basolateral membranes and mediates magnesium efflux.

However, without functional evidence gathering citations, I cannot provide the comprehensive, well-cited research report requested. The technical limitations prevented completion of this task despite extensive literature retrieval efforts.

Aspect CNNM4 summary Key details / examples Sources
Gene/protein identity CNNM4 is a conserved member of the CNNM/CorB (ACDP) family of divalent cation transport mediators Matches the UniProt description for the dog ortholog: ACDP family protein with CBS-domain architecture and CNNM/CorB-type transmembrane transporter features; mammalian literature consistently treats CNNM4 as the CNNM4 magnesium transporter ortholog Yamazaki et al., 2013, https://doi.org/10.1371/journal.pgen.1003983; Chen et al., 2021, https://doi.org/10.1038/s41467-021-24282-7; Franken et al., 2022, https://doi.org/10.1007/s00018-022-04442-8
Protein structure / domains Integral membrane protein with DUF21/CNNM transmembrane region and cytosolic CBS-pair (Bateman) domains; belongs to CorB/CNNM structural lineage UniProt annotation lists ACDP/CNNM-related domains plus CBS domains; structural work on archaeal CorB, the prokaryotic homolog, supports a transmembrane Mg2+-handling module coupled to cytosolic CBS domains that sense Mg-ATP and regulate conformation Chen et al., 2021, https://doi.org/10.1038/s41467-021-24282-7; Franken et al., 2022, https://doi.org/10.1007/s00018-022-04442-8
Primary molecular function Magnesium transport mediator, best supported as a Mg2+ efflux protein in epithelia Mouse and cell studies identified CNNM4 as the basolateral Mg2+ extrusion system required for transcellular Mg2+ transport across epithelia; recent physiological reviews still describe CNNM4 as a likely/potential Na+/Mg2+ exchanger mediating Mg2+ efflux in colon Yamazaki et al., 2013, https://doi.org/10.1371/journal.pgen.1003983; Kröse & de Baaij, 2024, https://doi.org/10.1093/ndt/gfae134
Substrate specificity Primary substrate is Mg2+ CNNM4 is repeatedly discussed in the Mg2+ transport literature as a magnesium transporter; disease and knockout phenotypes are explained by altered magnesium handling rather than transport of another defined physiological substrate Yamazaki et al., 2013, https://doi.org/10.1371/journal.pgen.1003983; Franken et al., 2022, https://doi.org/10.1007/s00018-022-04442-8; Kröse & de Baaij, 2024, https://doi.org/10.1093/ndt/gfae134
Transport mechanism Most direct epithelial evidence supports basolateral Mg2+ extrusion, likely coupled to extracellular Na+; broader CNNM mechanism remains actively debated Yamazaki et al. reported imaging evidence that CNNM4 extrudes intracellular Mg2+ in exchange for extracellular Na+; later reviews note that CNNM proteins remain mechanistically debated, but structural/functional data from CorB homologs support direct Mg2+ transport capacity; CNNMs may also influence TRPM7-dependent divalent cation influx in parallel Yamazaki et al., 2013, https://doi.org/10.1371/journal.pgen.1003983; Schäffers et al., 2018, https://doi.org/10.1152/ajprenal.00634.2017; Chen et al., 2021, https://doi.org/10.1038/s41467-021-24282-7; Bai et al., 2021, https://doi.org/10.1371/journal.pbio.3001496
Subcellular localization Basolateral plasma membrane of polarized epithelial cells Strong localization in intestinal epithelia and ameloblasts at the basolateral membrane explains its role in exporting Mg2+ from epithelial cells toward blood/interstitium during transcellular transport Yamazaki et al., 2013, https://doi.org/10.1371/journal.pgen.1003983
Tissue expression / physiological sites Best-established in intestine/colon and ameloblasts; less evidence for kidney than CNNM2 CNNM4 is strongly expressed in intestinal epithelia and contributes to intestinal Mg absorption; knockout mice showed intestinal malabsorption and hypomagnesemia. CNNM4 is also present in ameloblasts, linking Mg homeostasis to enamel maturation. Reviews distinguish CNNM4 from CNNM2, which is more renal Yamazaki et al., 2013, https://doi.org/10.1371/journal.pgen.1003983; Kröse & de Baaij, 2024, https://doi.org/10.1093/ndt/gfae134; de Baaij, 2023, https://doi.org/10.1152/ajprenal.00298.2022
Biological role in organismal Mg homeostasis Supports transcellular intestinal Mg absorption by mediating basolateral Mg exit from absorptive epithelia Loss of CNNM4 causes hypomagnesemia in mice due to intestinal malabsorption; this places CNNM4 downstream of apical Mg entry pathways such as TRPM6/7 and upstream of Mg delivery to the internal milieu Yamazaki et al., 2013, https://doi.org/10.1371/journal.pgen.1003983; Kröse & de Baaij, 2024, https://doi.org/10.1093/ndt/gfae134
Regulation by cytosolic ligands / domains CBS-pair domains act as regulatory modules that bind Mg-ATP and alter conformation Structural and comparative studies indicate CNNM/CorB CBS domains are not passive motifs: they bind Mg-ATP and are linked to conformational changes relevant to transport regulation Chen et al., 2021, https://doi.org/10.1038/s41467-021-24282-7; Bai et al., 2021, https://doi.org/10.1371/journal.pbio.3001496
Protein interaction network CNNM4 participates in the emerging PRL–CNNM–TRPM regulatory network CNNM proteins bind phosphatases of regenerating liver (PRLs) through the CBS domains; PRL binding is widely interpreted as inhibiting CNNM Mg2+ efflux activity. CNNMs also interact with TRPM7 and can stimulate TRPM7-dependent divalent cation entry, indicating CNNM4 may coordinate efflux and influx arms of Mg homeostasis rather than acting in isolation Bai et al., 2021, https://doi.org/10.1371/journal.pbio.3001496; Hardy et al., 2023, https://doi.org/10.1073/pnas.2221083120; Funato et al., 2024, https://doi.org/10.1038/s41598-024-76269-1; Jolly & Blackburn, 2025, https://doi.org/10.3390/ijms26041528
Signaling pathways / downstream biology Linked to TRPM7 signaling, cellular bioenergetics, adipocyte thermogenesis, macrophage polarization, and mTORC2 activation In adipocytes, cold-induced ADRB3–PKA–CREB signaling upregulates CNNM4, promoting Mg secretion; extracellular Mg then promotes M2 macrophage polarization through mTORC2 signaling. More broadly, Mg homeostasis proteins including CNNMs intersect with PRL/TRPM7-dependent metabolic signaling Hardy et al., 2023, https://doi.org/10.1073/pnas.2221083120; Zhang et al., 2024, https://doi.org/10.1002/advs.202401140; Jolly & Blackburn, 2025, https://doi.org/10.3390/ijms26041528
Disease associations Jalili syndrome; hypomagnesemia/intestinal malabsorption in experimental models; emerging links to cancer and metabolic disease Human CNNM4 mutations cause Jalili syndrome, characterized by cone-rod dystrophy and amelogenesis imperfecta. In mice, Cnnm4 loss causes hypomagnesemia and enamel defects. Recent literature also implicates altered CNNM4 expression in obesity-related thermogenic dysfunction and in cancers such as cholangiocarcinoma Parry et al., 2009, https://doi.org/10.1016/j.ajhg.2009.01.009; Yamazaki et al., 2013, https://doi.org/10.1371/journal.pgen.1003983; Prasov et al., 2020, https://doi.org/10.1002/ajmg.a.61484; Zhang et al., 2024, https://doi.org/10.1002/advs.202401140; Mercado-Gómez et al., 2026, https://doi.org/10.1136/gutjnl-2024-333255
Phenotypic evidence from models Knockout/deficiency phenotypes strongly support physiological relevance Cnnm4-knockout mice develop hypomagnesemia due to impaired intestinal Mg absorption and show defective amelogenesis, while disease-associated missense variants abolish Mg extrusion activity in assays Yamazaki et al., 2013, https://doi.org/10.1371/journal.pgen.1003983
Recent developments (2023–2025) Field has shifted from “is CNNM4 a transporter?” to “how does CNNM4 integrate transport with signaling and disease?” 2023 renal Mg review frames CNNM-family function within unresolved basolateral Mg extrusion; 2024 magnesium biology review positions CNNM4 as a colon Na+/Mg2+ exchanger candidate; 2024 adipocyte study shows regulated Mg secretion with immune/metabolic consequences; 2024 PRL–CNNM screening paper highlights therapeutic targeting of the PRL–CNNM interaction; 2025 PACT review integrates PRL, ARL, CNNM, and TRPM proteins into a unified Mg homeostasis network de Baaij, 2023, https://doi.org/10.1152/ajprenal.00298.2022; Kröse & de Baaij, 2024, https://doi.org/10.1093/ndt/gfae134; Zhang et al., 2024, https://doi.org/10.1002/advs.202401140; Funato et al., 2024, https://doi.org/10.1038/s41598-024-76269-1; Jolly & Blackburn, 2025, https://doi.org/10.3390/ijms26041528
Relevance to dog CNNM4 (A0A8I3PI07) Direct canine functional studies were not identified, so annotation is inferred from strong mammalian orthology Because the dog protein carries the expected CNNM/ACDP and CBS-domain architecture and CNNM4 function is well conserved across mammals, the most defensible annotation is that canine CNNM4 is a basolateral Mg2+ transport mediator important for epithelial Mg handling, likely in intestine and enamel/retina-associated tissues UniProt record provided by user; mammalian orthology supported by Yamazaki et al., 2013, https://doi.org/10.1371/journal.pgen.1003983; Franken et al., 2022, https://doi.org/10.1007/s00018-022-04442-8

Table: This table compiles the main structural, functional, localization, pathway, disease, and recent literature findings relevant to CNNM4. It is designed to support functional annotation of the canine CNNM4 ortholog by grounding inference in experimentally studied mammalian and family-level evidence.

Artifacts

Citations

  1. https://doi.org/10.1371/journal.pgen.1003983;
  2. https://doi.org/10.1038/s41467-021-24282-7;
  3. https://doi.org/10.1007/s00018-022-04442-8
  4. https://doi.org/10.1093/ndt/gfae134
  5. https://doi.org/10.1007/s00018-022-04442-8;
  6. https://doi.org/10.1152/ajprenal.00634.2017;
  7. https://doi.org/10.1371/journal.pbio.3001496
  8. https://doi.org/10.1371/journal.pgen.1003983
  9. https://doi.org/10.1093/ndt/gfae134;
  10. https://doi.org/10.1152/ajprenal.00298.2022
  11. https://doi.org/10.1371/journal.pbio.3001496;
  12. https://doi.org/10.1073/pnas.2221083120;
  13. https://doi.org/10.1038/s41598-024-76269-1;
  14. https://doi.org/10.3390/ijms26041528
  15. https://doi.org/10.1002/advs.202401140;
  16. https://doi.org/10.1016/j.ajhg.2009.01.009;
  17. https://doi.org/10.1002/ajmg.a.61484;
  18. https://doi.org/10.1136/gutjnl-2024-333255
  19. https://doi.org/10.1152/ajprenal.00298.2022;

📄 View Raw YAML

 
id: A0A8I3PI07
gene_symbol: CNNM4
product_type: PROTEIN
status: DRAFT
taxon:
  id: NCBITaxon:9615
  label: Canis lupus familiaris
description: >-
  CNNM4 (Cyclin and CBS Domain Divalent Metal Cation Transport Mediator 4) is a
  multi-pass transmembrane protein belonging to the ancient conserved domain protein
  (ACDP) family. The 796-amino-acid protein contains a signal peptide, an N-terminal
  immunoglobulin-like domain, a CNNM transmembrane domain with four transmembrane
  helices, a cystathionine-beta-synthase (CBS) domain pair that binds Mg2+-ATP, and
  a C-terminal cyclic nucleotide binding homology (CNBH) domain. CNNM4 functions
  as a magnesium efflux transporter at the basolateral membrane of epithelial cells,
  mediating Mg2+ extrusion from cells. In mammals, CNNM4 is expressed in intestinal
  epithelial cells where it is critical for magnesium homeostasis. The protein has
  also been reported to have sodium ion transmembrane transporter activity. Mutations
  in the human ortholog cause Jalili syndrome, characterized by cone-rod dystrophy
  and amelogenesis imperfecta. CNNM4 forms oligomeric complexes and its transport
  activity is regulated by intracellular Mg2+-ATP binding to the CBS domain pair.
existing_annotations:
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic annotation placing CNNM4 as active in the plasma membrane, based
      on ortholog data from mouse and human CNNM family members as well as C. elegans
      and Drosophila orthologs. CNNM4 is a multi-pass transmembrane protein with four
      transmembrane helices in the CNNM domain (residues 178-358). The UniProt record
      confirms cell membrane localization. Human CNNM4 localizes to the basolateral
      plasma membrane of intestinal epithelial cells.
    action: ACCEPT
    reason: >-
      Plasma membrane localization is well established for CNNM4 orthologs. The protein
      has a signal peptide and four transmembrane helices, consistent with an integral
      plasma membrane protein. The IBA annotation is supported by multiple ortholog
      sources including mouse and human CNNM4.
- term:
    id: GO:0010960
    label: magnesium ion homeostasis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic annotation for involvement in magnesium ion homeostasis, based on
      orthologs including mouse Cnnm4 and human CNNM4. CNNM4 is a magnesium efflux
      transporter, and its role in Mg2+ homeostasis is well established. Loss-of-function
      mutations in human CNNM4 cause Jalili syndrome with hypomagnesemia as a feature,
      demonstrating the protein's critical role in systemic magnesium homeostasis.
    action: ACCEPT
    reason: >-
      Magnesium ion homeostasis is a core biological process for CNNM4. The protein
      directly mediates Mg2+ efflux, and its dysfunction leads to magnesium imbalance.
      This annotation is well supported by ortholog data.
- term:
    id: GO:0015081
    label: sodium ion transmembrane transporter activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic annotation for sodium ion transmembrane transporter activity based
      on mouse Cnnm4 ortholog data. Some studies have suggested that CNNM family members
      can mediate Na+ transport or that Mg2+ extrusion by CNNM proteins is coupled to
      Na+ influx. However, the primary and best-characterized transport activity of CNNM4
      is magnesium transport. The sodium transport activity may reflect a coupled or
      secondary activity rather than an independent transport function.
    action: UNDECIDED
    reason: >-
      The sodium ion transport activity of CNNM4 is less well established than its
      magnesium transport function. While some evidence supports Na+-coupled Mg2+ transport
      by CNNM family members, the mechanistic details remain debated and the sodium
      transport may be secondary to the primary Mg2+ efflux function. Without access
      to the primary experimental literature on this specific activity, marking as
      UNDECIDED is appropriate.
- term:
    id: GO:0015095
    label: magnesium ion transmembrane transporter activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic annotation for magnesium ion transmembrane transporter activity based
      on mouse Cnnm4 ortholog data. This is the primary characterized molecular function
      of CNNM4. The protein mediates Mg2+ efflux across the plasma membrane, and this
      activity is essential for intestinal magnesium absorption in mammals.
    action: ACCEPT
    reason: >-
      Magnesium ion transmembrane transporter activity is the core molecular function
      of CNNM4. This is well supported by experimental evidence in orthologs showing
      that CNNM4 mediates cellular Mg2+ extrusion. The IBA annotation correctly captures
      the primary function of this protein.
- term:
    id: GO:0015693
    label: magnesium ion transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic annotation for involvement in magnesium ion transport, based on mouse
      Cnnm4 ortholog data. CNNM4 directly mediates Mg2+ efflux, so involvement in
      magnesium ion transport is a direct consequence of its transporter activity.
    action: ACCEPT
    reason: >-
      Magnesium ion transport is a core biological process for CNNM4, directly reflecting
      its molecular function as a Mg2+ transporter. Well supported by ortholog evidence.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Combined IEA annotation for plasma membrane localization based on human ortholog
      Q6P4Q7 (CNNM4) via Ensembl, UniProt SubCell mapping, and PANTHER. Consistent
      with the IBA annotation above and the protein's domain architecture (signal peptide
      plus four transmembrane helices).
    action: ACCEPT
    reason: >-
      Plasma membrane localization is well established for CNNM4. This IEA annotation
      is consistent with the IBA annotation and the protein's structural features as a
      multi-pass transmembrane protein with a signal peptide.
- term:
    id: GO:0010960
    label: magnesium ion homeostasis
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Combined IEA annotation for magnesium ion homeostasis based on InterPro ACDP
      family (IPR045095) and PANTHER. This is consistent with the IBA annotation for
      the same term and reflects the well-established role of CNNM4 in Mg2+ homeostasis.
    action: ACCEPT
    reason: >-
      Consistent with the IBA annotation and the known biology of CNNM4 as a magnesium
      efflux transporter critical for Mg2+ homeostasis. The InterPro ACDP family
      classification correctly predicts this function.
- term:
    id: GO:0015693
    label: magnesium ion transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000118
  qualifier: involved_in
  review:
    summary: >-
      TreeGrafter-generated annotation for magnesium ion transport. Consistent with the
      IBA annotation for the same term and the core function of CNNM4 as a magnesium
      transporter.
    action: ACCEPT
    reason: >-
      This TreeGrafter annotation is consistent with the IBA annotation and accurately
      reflects the core biological process of CNNM4. Magnesium ion transport is the
      primary physiological function of this protein.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000104
  qualifier: located_in
  review:
    summary: >-
      UniRule-based annotation for membrane localization. This is an extremely broad
      cellular component term. CNNM4 is indeed an integral membrane protein with four
      transmembrane helices, but more specific CC terms (plasma membrane, basolateral
      plasma membrane) are already annotated.
    action: ACCEPT
    reason: >-
      While very broad, this annotation is not incorrect. CNNM4 is an integral membrane
      protein. More specific CC terms are already present (GO:0005886 plasma membrane,
      GO:0016323 basolateral plasma membrane).
- term:
    id: GO:0022857
    label: transmembrane transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Combined IEA annotation for transmembrane transporter activity based on PANTHER
      and UniRule. This is a broad parent term of the more specific magnesium and sodium
      ion transmembrane transporter activities. CNNM4 is a transmembrane transporter,
      so this is accurate but uninformative given the more specific MF annotations.
    action: KEEP_AS_NON_CORE
    reason: >-
      This is a valid but very general molecular function term. The more specific
      GO:0015095 (magnesium ion transmembrane transporter activity) better captures
      the core function. This broad term adds no information beyond what the specific
      terms already provide.
- term:
    id: GO:0035725
    label: sodium ion transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: >-
      Logical inference (IC) annotation for sodium ion transmembrane transport, derived
      from the sodium ion transmembrane transporter activity annotation (GO:0015081).
      This is a downstream inference -- if the protein enables sodium ion transmembrane
      transporter activity, it is logically involved in sodium ion transmembrane transport.
    action: UNDECIDED
    reason: >-
      This annotation is logically derived from GO:0015081 (sodium ion transmembrane
      transporter activity). Since the sodium transporter activity annotation itself
      is UNDECIDED due to limited evidence for CNNM4 sodium transport, this derived
      annotation inherits the same uncertainty.
- term:
    id: GO:0055085
    label: transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: >-
      Logical inference annotation for transmembrane transport, derived from the
      transmembrane transporter activity annotation (GO:0022857). This is a very broad
      biological process term.
    action: KEEP_AS_NON_CORE
    reason: >-
      This is a valid but extremely general annotation logically derived from the
      transmembrane transporter activity MF annotation. The more specific magnesium
      ion transport annotation better captures the core process.
- term:
    id: GO:1903830
    label: magnesium ion transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: >-
      Logical inference annotation for magnesium ion transmembrane transport, derived
      from the magnesium ion transmembrane transporter activity annotation (GO:0015095).
      This is the specific biological process corresponding to the core molecular function
      of CNNM4.
    action: ACCEPT
    reason: >-
      This annotation is logically derived from GO:0015095 (magnesium ion transmembrane
      transporter activity) which is well supported. Magnesium ion transmembrane transport
      is a core biological process for CNNM4 and this inference is correct.
- term:
    id: GO:0015081
    label: sodium ion transmembrane transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Combined IEA annotation for sodium ion transmembrane transporter activity based
      on mouse ortholog Q69ZF7 (Cnnm4) via Ensembl and PANTHER. This is a duplicate
      source for the same function annotated by IBA. As with the IBA annotation, the
      sodium transport activity of CNNM4 is less well established than its magnesium
      transport function.
    action: UNDECIDED
    reason: >-
      Same uncertainty as the IBA annotation for this term. The sodium transport activity
      of CNNM4 remains debated and may reflect a coupled mechanism rather than an
      independent transport function. Without deep research literature access, marking
      as UNDECIDED is appropriate.
- term:
    id: GO:0015095
    label: magnesium ion transmembrane transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Combined IEA annotation for magnesium ion transmembrane transporter activity based
      on mouse ortholog Q69ZF7 (Cnnm4) via Ensembl and PANTHER. This is a duplicate
      source for the same function annotated by IBA.
    action: ACCEPT
    reason: >-
      Consistent with the IBA annotation and the well-established core function of CNNM4
      as a magnesium efflux transporter.
- term:
    id: GO:0016323
    label: basolateral plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Ensembl Compara ortholog transfer annotation for basolateral plasma membrane
      localization, based on mouse ortholog Q69ZF7 (Cnnm4). Human and mouse CNNM4
      localizes specifically to the basolateral plasma membrane of intestinal epithelial
      cells, where it mediates Mg2+ efflux into the interstitial space. This is the
      most specific and informative CC annotation for CNNM4.
    action: ACCEPT
    reason: >-
      Basolateral plasma membrane localization is well established for mammalian CNNM4.
      The protein mediates vectorial Mg2+ transport from the apical to basolateral side
      of intestinal epithelial cells, and its basolateral localization is essential for
      this function. This is the most informative cellular component annotation and
      represents the primary site of CNNM4 activity.
- term:
    id: GO:0030003
    label: intracellular monoatomic cation homeostasis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl Compara annotation for intracellular monoatomic cation homeostasis, based
      on human ortholog Q6P4Q7. CNNM4 mediates Mg2+ efflux and thereby contributes to
      intracellular cation homeostasis. This is a broader parent term of magnesium ion
      homeostasis.
    action: KEEP_AS_NON_CORE
    reason: >-
      This is a valid but broad biological process annotation. CNNM4 contributes to
      intracellular cation homeostasis primarily through its Mg2+ efflux activity. The
      more specific GO:0010960 (magnesium ion homeostasis) better captures the core
      function.
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: >-
      Ensembl Compara annotation indicating CNNM4 is part of a protein-containing
      complex, based on human ortholog Q6P4Q7. CNNM family members are known to form
      oligomeric complexes (likely dimers or trimers) and to interact with phosphatases
      of regenerating liver (PRL/PTP4A) family members. However, the term
      protein-containing complex is extremely broad and uninformative.
    action: KEEP_AS_NON_CORE
    reason: >-
      While CNNM4 does form oligomeric complexes and interacts with PRL phosphatases,
      the term protein-containing complex is too broad to be informative. A more specific
      complex term would be needed to capture the meaningful biology. Keeping as non-core
      rather than removing since the protein does indeed participate in complexes.
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000104
  title: Electronic Gene Ontology annotations created by transferring manual GO annotations
    between related proteins based on shared sequence features
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: GO_REF:0000118
  title: TreeGrafter-generated GO annotations
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
core_functions:
  - description: >-
      CNNM4 is a magnesium efflux transporter that mediates Mg2+ extrusion across the
      basolateral plasma membrane of epithelial cells. The protein contains a CNNM
      transmembrane domain with four transmembrane helices that forms the transport
      pathway, and a cytoplasmic CBS domain pair that binds Mg2+-ATP to regulate transport
      activity. CNNM4 localizes to the basolateral membrane where it functions in
      transcellular magnesium absorption, particularly in intestinal epithelium. Loss
      of function causes Jalili syndrome (cone-rod dystrophy with amelogenesis imperfecta)
      in humans, highlighting its essential role in magnesium homeostasis for eye and
      tooth development. CNNM4 forms oligomeric complexes and interacts with PRL (PTP4A)
      family phosphatases which regulate its activity.
    molecular_function:
      id: GO:0015095
      label: magnesium ion transmembrane transporter activity
    directly_involved_in:
      - id: GO:1903830
        label: magnesium ion transmembrane transport
      - id: GO:0010960
        label: magnesium ion homeostasis
    locations:
      - id: GO:0016323
        label: basolateral plasma membrane