{"uniprot":"Q9BXT2","gene":"CACNG6","name":"Voltage-dependent calcium channel gamma-6 subunit","organism":"Homo sapiens (Human)","status":"dark","length":260,"sequence":"MMWSNFFLQEENRRRGAAGRRRAHGQGRSGLTPEREGKVKLALLLAAVGATLAVLSVGTEFWVELNTYKANGSAVCEAAHLGLWKACTKRLWQADVPVDRDTCGPAELPGEANCTYFKFFTTGENARIFQRTTKKEVNLAAAVIAVLGLAVMALGCLCIIMVLSKGAEFLLRVGAVCFGLSGLLLLVSLEVFRHSVRALLQRVSPEPPPAPRLTYEYSWSLGCGVGAGLILLLGAGCFLLLTLPSWPWGSLCPKRGHRAT","function_summary":"A multi-pass membrane auxiliary subunit of voltage-gated calcium channel complexes in human cells that uses a claudin-like tetraspan scaffold to regulate channel assembly, trafficking, and gating. By embedding within the plasma membrane and concentrating in specialized membrane domains such as T-tubules, it fine-tunes calcium current amplitude and kinetics—particularly in excitable tissues—thereby shaping calcium influx pathways through allosteric modulation of pore-forming channel subunits.","plain_language":"CACNG6 has barely been studied. The model's best guess: A multi-pass membrane auxiliary subunit of voltage-gated calcium channel complexes in human cells that uses a claudin-like tetraspan scaffold to regulate channel assembly, trafficking, and gating. By embedding within the plasma membrane and concentrating in specialized membrane domains such as T-tubules, it fine-tunes calcium current amplitude and kinetics—particularly in excitable tissues—thereby shaping calcium influx pathways through allosteric modulation of pore-forming channel subunits.","uniprot_summary":"Regulatory subunit of voltage-gated calcium channels.","go_terms":{"molecular_function":[{"id":"GO:0005246","label":"calcium channel regulator activity"}],"biological_process":[{"id":"GO:1903169","label":"regulation of calcium ion transmembrane transport"}],"cellular_component":[{"id":"GO:0030315","label":"T-tubule"},{"id":"GO:0005891","label":"voltage-gated calcium channel complex"}]},"interpro":[{"id":"IPR008370","name":"Voltage-dependent calcium channel, gamma-6 subunit","type":"family","start":2,"end":13},{"id":"IPR008370","name":"Voltage-dependent calcium channel, gamma-6 subunit","type":"family","start":14,"end":32},{"id":"IPR008368","name":"Voltage-dependent calcium channel, gamma subunit","type":"family","start":46,"end":64},{"id":"IPR004031","name":"PMP-22/EMP/MP20/Claudin","type":"family","start":48,"end":239},{"id":"IPR008370","name":"Voltage-dependent calcium channel, gamma-6 subunit","type":"family","start":65,"end":76},{"id":"IPR008370","name":"Voltage-dependent calcium channel, gamma-6 subunit","type":"family","start":91,"end":109},{"id":"IPR008368","name":"Voltage-dependent calcium channel, gamma subunit","type":"family","start":181,"end":200},{"id":"IPR008368","name":"Voltage-dependent calcium channel, gamma subunit","type":"family","start":215,"end":236},{"id":"IPR008370","name":"Voltage-dependent calcium channel, gamma-6 subunit","type":"family","start":237,"end":254}],"reasoning":"I begin with the InterPro architecture. The N-terminus carries multiple gamma-6–specific signatures: IPR008370 (Voltage-dependent calcium channel, gamma-6 subunit, residues 2–13), followed shortly by another gamma-6 hallmark IPR008370 at residues 14–32. This tandem of gamma-6 family motifs is followed by additional gamma-subunit family markers IPR008368 (Voltage-dependent calcium channel, gamma subunit, residues 46–64 and 181–200), establishing that the polypeptide belongs to the auxiliary gamma class of voltage-gated calcium channel complexes. The core of the protein is encompassed by IPR004031 (PMP-22/EMP/MP20/Claudin family, residues 48–239), a four-pass membrane superfamily whose members form compact tetraspan architectures that modulate membrane protein complexes rather than conduct ions themselves. Within this scaffold, there are further gamma-6–specific segments (IPR008370 at residues 65–76 and 91–109) and gamma-subunit signatures (IPR008368 at residues 215–236), culminating in a terminal gamma-6 block (IPR008370 at residues 237–254). The ordered layout—N-terminal gamma-6 identity motifs, a central claudin-like tetraspan core, and C-terminal gamma-6/gamma repeats—defines a membrane-embedded auxiliary subunit that assembles with pore-forming calcium channel alpha1 subunits to tune gating and trafficking.\n\nThis architecture dictates the molecular function. Claudin-like tetraspan modules lack catalytic residues and instead create lateral interaction surfaces that allosterically regulate partner channels. The multiplicity of gamma-6/gamma family signatures causes the protein to act as a calcium channel auxiliary subunit that modulates voltage-gated Ca2+ channel behavior. This directly supports GO:0005246 calcium channel regulator activity as the molecular function: the four-pass scaffold stabilizes and tunes the alpha1 channel complex rather than conducting ions.\n\nFrom this regulatory role, the biological process follows. By altering channel open probability, kinetics, and surface expression, the gamma architecture constrains Ca2+ influx pathways. Such modulation maps to GO:1903169 regulation of calcium ion transmembrane transport—adjusting Ca2+ entry in excitable membranes and secretory cells through allosteric control of the channel complex.\n\nCellular context is implied by both the tetraspan fold and the gamma-6 identity. The PMP-22/EMP/MP20/Claudin superfamily embeds stably in the plasma membrane, and gamma subunits of calcium channels are canonical components of the channel assembly at the cell surface. This places the protein within the GO:0005891 voltage-gated calcium channel complex and situates it at specialized membrane subdomains. In striated muscle, channel assemblies concentrate in transverse-tubule systems, aligning with GO:0030315 T-tubule. The multi-pass membrane nature inferred from IPR004031 and the gamma-6/gamma signatures coherently explains a cell-membrane, multi-pass topology.\n\nMechanistically, the protein likely forms a lateral tetraspan platform that couples to alpha1 subunits (e.g., CACNA1C and CACNA1D) and auxiliary beta subunits to stabilize channel assembly and tune gating. By shaping the local lipid and protein environment, it can bias voltage sensors and pore gating equilibria, thereby dampening or refining Ca2+ currents in excitable tissues. I hypothesize that it associates with beta subunits (CACNB family) and alpha2delta subunits to coordinate trafficking and surface density, and that in muscle it co-clusters with L-type channel complexes within T-tubules to regulate excitation–contraction coupling fidelity.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-Q9BXT2.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/Q9BXT2"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/Q9BXT2/entry","atlas":"/p/Q9BXT2"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}