{"uniprot":"Q9BY10","gene":"SLC46A2","name":"Thymic stromal cotransporter homolog","organism":"Homo sapiens (Human)","status":"dark","length":475,"sequence":"MSPEVTCPRRGHLPRFHPRTWVEPVVASSQVAASLYDAGLLLVVKASYGTGGSSNHSASPSPRGALEDQQQRAISNFYIIYNLVVGLSPLLSAYGLGWLSDRYHRKISICMSLLGFLLSRLGLLLKVLLDWPVEVLYGAAALNGLFGGFSAFWSGVMALGSLGSSEGRRSVRLILIDLMLGLAGFCGSMASGHLFKQMAGHSGQGLILTACSVSCASFALLYSLLVLKVPESVAKPSQELPAVDTVSGTVGTYRTLDPDQLDQQYAVGHPPSPGKAKPHKTTIALLFVGAIIYDLAVVGTVDVIPLFVLREPLGWNQVQVGYGMAAGYTIFITSFLGVLVFSRCFRDTTMIMIGMVSFGSGALLLAFVKETYMFYIARAVMLFALIPVTTIRSAMSKLIKGSSYGKVFVILQLSLALTGVVTSTLYNKIYQLTMDMFVGSCFALSSFLSFLAIIPISIVAYKQVPLSPYGDIIEK","function_summary":"A multi-pass membrane protein that adopts a transporter-like fold to build a membrane-anchored platform for assembling innate immune signaling complexes. By using extensive membrane-embedded helices and cytosolic interaction surfaces, it binds and organizes receptors and adaptors at the cell surface to enhance NOD-driven pathways. Its architecture favors scaffolded protein binding over classical solute transport, thereby promoting assembly and stability of signaling assemblies that elevate pathway output at the plasma membrane.","plain_language":"SLC46A2 has barely been studied. The model's best guess: A multi-pass membrane protein that adopts a transporter-like fold to build a membrane-anchored platform for assembling innate immune signaling complexes. By using extensive membrane-embedded helices and cytosolic interaction surfaces, it binds and organizes receptors and adaptors at the cell surface to enhance NOD-driven pathways.","uniprot_summary":"May be involved in NOD1 and NOD2 signaling pathway.","go_terms":{"molecular_function":[{"id":"GO:0005515","label":"protein binding"}],"biological_process":[{"id":"GO:0070426","label":"positive regulation of nucleotide-binding oligomerization domain containing signaling pathway"}],"cellular_component":[{"id":"GO:0009986","label":"cell surface"}]},"interpro":[{"id":"IPR036259","name":"MFS transporter superfamily","type":"homologous_superfamily","start":52,"end":457},{"id":"IPR011701","name":"Major facilitator superfamily","type":"family","start":86,"end":344},{"id":"IPR001958","name":"Tetracycline resistance protein TetA/multidrug resistance protein MdtG-like","type":"family","start":177,"end":198},{"id":"IPR001958","name":"Tetracycline resistance protein TetA/multidrug resistance protein MdtG-like","type":"family","start":347,"end":368},{"id":"IPR001958","name":"Tetracycline resistance protein TetA/multidrug resistance protein MdtG-like","type":"family","start":407,"end":430}],"reasoning":"I begin with the InterPro architecture. The polypeptide core is defined by IPR036259 (MFS transporter superfamily, residues 52–457) and IPR011701 (Major facilitator superfamily, residues 86–344), establishing a canonical major facilitator superfamily fold that typically forms 12 transmembrane helices arranged as two pseudosymmetric six-helix bundles. Three independent TetA/MdtG-like signatures—IPR001958 (Tetracycline resistance protein TetA/multidrug resistance protein MdtG-like, residues 177–198), IPR001958 (residues 347–368), and IPR001958 (residues 407–430)—map to internal helices that are characteristic of drug/H+ antiporters. This composite architecture causes alternating-access transport through a proton-motive-force-coupled mechanism, but in many eukaryotic MFS members the fold is repurposed for signaling rather than solute translocation.\n\nFrom this scaffold, I infer molecular function first. The MFS fold is inherently membrane-embedded and interaction-prone; its cytosolic loops and termini commonly mediate protein-protein contacts that regulate pathway assembly. This structural propensity supports GO:0005515 protein binding as the operative molecular function, with binding surfaces provided by cytosolic loops and termini that recruit signaling partners rather than catalyzing soluble reactions.\n\nThe biological process follows from how this transporter-like scaffold modulates innate immune signaling. The membrane-integrated MFS platform at the cell surface can nucleate and stabilize assemblies that drive NOD-like receptor pathways. By concentrating receptors and adaptors at membrane-proximal hubs, the protein enhances signal initiation and propagation, aligning with GO:0070426 positive regulation of nucleotide-binding oligomerization domain containing signaling pathway. The TetA/MdtG-like motifs do not enforce classical efflux activity here; instead, they tune the conformational landscape that favors adaptor docking and signalosome formation.\n\nCellular location is dictated by the fold and topology. The extensive MFS core and multi-pass topology place the protein in the plasma membrane, consistent with a cell-surface resident that organizes signaling complexes. This supports GO:0009986 cell surface and the experimentally observed multi-pass membrane localization.\n\nMechanistically, I hypothesize that the MFS core forms a rigid yet responsive platform that binds cytosolic adaptors and receptors to potentiate NOD pathway output. At the plasma membrane, the transporter-like helices create lateral membrane corrals for NOD1/NOD2 and their downstream partners. By stabilizing assemblies with RIPK2 and ubiquitin ligases, the complex enhances NF-κB and MAPK activation. Likely interaction partners therefore include NOD1 and NOD2 themselves, the adaptor RIPK2, membrane-proximal ubiquitin machinery (e.g., TRAF6 and XIAP), and possibly clathrin/adaptor modules that regulate surface residency. This membrane-anchored, binding-driven mechanism explains how a repurposed MFS architecture positively regulates NOD-like receptor signaling at the cell surface.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-Q9BY10.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/Q9BY10"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/Q9BY10/entry","atlas":"/p/Q9BY10"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}