{"uniprot":"Q9NRU3","gene":"CNNM1","name":"Metal transporter CNNM1","organism":"Homo sapiens (Human)","status":"dark","length":951,"sequence":"MAAAAAAAAAVGVRLRDCCSRGAVLLLFFSLSPRPPAAAAWLLGLRPEDTAGGRVSLEGGTLRAAEGTSFLLRVYFQPGPPATAAPVPSPTLNSGENGTGDWAPRLVFIEEPPGGGGVAPSAVPTRPPGPQRCREQSDWASDVEVLGPLRPGGVAGSALVQVRVRELRKGEAERGGAGGGGKLFSLCAWDGRAWHHHGAAGGFLLRVRPRLYGPGGDLLPPAWLRALGALLLLALSALFSGLRLSLLSLDPVELRVLRNSGSAAEQEQARRVQAVRGRGTHLLCTLLLGQAGANAALAGWLYTSLPPGFGGTGEDYSEEGIHFPWLPALVCTGAVFLGAEICPYSVCSRHGLAIASHSVCLTRLLMAAAFPVCYPLGRLLDWALRQEISTFYTREKLLETLRAADPYSDLVKEELNIIQGALELRTKVVEEVLTPLGDCFMLRSDAVLDFATVSEILRSGYTRIPVYEGDQRHNIVDILFVKDLAFVDPDDCTPLLTVTRFYNRPLHCVFNDTRLDTVLEEFKKGKSHLAIVQRVNNEGEGDPFYEVMGIVTLEDIIEEIIKSEILDETDLYTDNRKKQRVPQRERKRHDFSLFKLSDTEMRVKISPQLLLATHRFMATEVEPFKSLYLSEKILLRLLKHPNVIQELKFDEKNKKAPEHYLYQRNRPVDYFVLLLQGKVEVEVGKEGLRFENGAFTYYGVPAIMTTACSDNDVRKVGSLAGSSVFLNRSPSRCSGLNRSESPNRERSDFGGSNTQLYSSSNNLYMPDYSVHILSDVQFVKITRQQYQNALTACHMDSSPQSPDMEAFTDGDSTKAPTTRGTPQTPKDDPAITLLNNRNSLPCSRSDGLRSPSEVVYLRMEELAFTQEEMTDFEEHSTQQLTLSPAAVPTRAASDSECCNINLDTETSPCSSDFEENVGKKLLRTLSGQKRKRSPEGERTSEDNSNLTPLIT","function_summary":"A human multi-pass membrane transporter that assembles into higher-order complexes and uses an extracellular immunoglobulin-like module, a transmembrane ion-conducting core, and a cytosolic CBS/CNBH regulatory tail to control cellular magnesium balance. By coupling transport to intracellular nucleotide and ion sensing, it modulates Mg2+ homeostasis and organizes membrane-associated assemblies that fine-tune ion handling and trafficking.","plain_language":"CNNM1 has barely been studied. The model's best guess: A human multi-pass membrane transporter that assembles into higher-order complexes and uses an extracellular immunoglobulin-like module, a transmembrane ion-conducting core, and a cytosolic CBS/CNBH regulatory tail to control cellular magnesium balance. By coupling transport to intracellular nucleotide and ion sensing, it modulates Mg2+ homeostasis and organizes membrane-associated assemblies that fine-tune ion handling and trafficking.","uniprot_summary":"Probable metal transporter.","go_terms":{"molecular_function":[{"id":"GO:0005515","label":"protein binding"}],"biological_process":[{"id":"GO:0010960","label":"magnesium ion homeostasis"}],"cellular_component":[{"id":"GO:0032991","label":"protein-containing complex"},{"id":"GO:0016021","label":"integral component of membrane"}]},"interpro":[{"id":"IPR046342","name":"CBS domain superfamily","type":"homologous_superfamily","start":412,"end":568},{"id":"IPR057492","name":"Metal transporter CNNM1/2/4, immunoglobulin-like domain","type":"domain","start":41,"end":208},{"id":"IPR002550","name":"CNNM, transmembrane domain","type":"domain","start":218,"end":414},{"id":"IPR044751","name":"Ion transporter-like, CBS domain","type":"domain","start":428,"end":553},{"id":"IPR000644","name":"CBS domain","type":"domain","start":502,"end":568},{"id":"IPR061271","name":"Metal transporter CNNM-like, C-terminal CNBH domain","type":"domain","start":576,"end":796},{"id":"IPR045095","name":"Ancient conserved domain protein family","type":"family","start":156,"end":813}],"reasoning":"I begin with the InterPro architecture and its order along the sequence. The N-terminus carries IPR057492 (Metal transporter CNNM1/2/4, immunoglobulin-like domain, residues 41–208), an Ig-like fold that typically mediates extracellular or luminal adhesion and protein–protein recognition, thereby priming the polypeptide for regulated assembly and trafficking. Immediately downstream lies IPR002550 (CNNM, transmembrane domain, residues 218–414), a multi-pass membrane core that forms the ion-translocation pathway characteristic of CNNM transporters. The C-terminal half is dominated by cytosolic regulatory modules: IPR046342 (CBS domain superfamily, residues 412–568) and IPR044751 (Ion transporter-like, CBS domain, residues 428–553) together with IPR000644 (CBS domain, residues 502–568) define a tandem CBS “BNH/CBS” regulatory cassette that senses adenylate and divalent cations to allosterically tune transport. This cassette is followed by IPR061271 (Metal transporter CNNM-like, C-terminal CNBH domain, residues 576–796), a cytosolic CBS-like module that completes the ancient conserved domain protein scaffold captured by IPR045095 (Ancient conserved domain protein family, residues 156–813). The ordered layout—extracellular Ig-like module → multi-pass transmembrane core → intracellular CBS/CNBH regulatory tail—creates a membrane transporter whose activity is gated by cytosolic nucleotide/ion sensing.\n\nThis architecture causes a molecular function centered on regulated ion handling rather than soluble catalysis. The multi-pass CNNM core provides the conduit, while the CBS/CNBH tail confers cation-responsive control; together they support ion translocation and assembly into higher-order complexes. The prominent Ig-like and CBS modules also enforce multivalent contacts with cytosolic partners, which substantiates GO:0005515 protein binding as a defining activity of this transporter-scaffold.\n\nFrom this molecular function, the biological process follows directly. CNNM-family transporters govern intracellular Mg2+ partitioning; the CBS/CNBH regulatory cassette is well-suited to couple transport to cellular energy and Mg2+ status. Consequently, the protein drives GO:0010960 magnesium ion homeostasis by modulating Mg2+ fluxes that set cytosolic and organellar pools.\n\nThe cellular context is dictated by the transmembrane core and the extracellular Ig-like domain. The presence of a multi-pass region and a luminal/extracellular Ig-like module places the protein in membranes as a multi-pass component, consistent with a membrane-resident transporter. The need for assembly and regulation via cytosolic CBS/CNBH domains further implies participation in macromolecular assemblies, aligning with GO:0032991 protein-containing complex. The membrane-embedded nature and trafficking signals support assignment to GO:0016021 integral component of membrane.\n\nMechanistically, I hypothesize that the Ig-like N-terminus organizes trafficking and surface complex formation, the CNNM transmembrane bundle forms the ion pathway, and the CBS/CNBH tail senses adenylates and Mg2+ to allosterically gate transport. This transporter likely nucleates complexes with cytosolic regulators and membrane partners to tune Mg2+ flux. Candidate interaction partners include other CNNM paralogs (forming hetero-oligomeric assemblies), phosphoinositide kinases/phosphatases that set membrane identity, and cytosolic Mg2+-sensing adaptors that dock onto the CBS/CNBH cassette. Such assemblies would coordinate membrane residency with Mg2+ homeostatic signaling.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-Q9NRU3.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/Q9NRU3"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/Q9NRU3/entry","atlas":"/p/Q9NRU3"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}