{"uniprot":"Q14952","gene":"KIR2DS3","name":"Killer cell immunoglobulin-like receptor 2DS3","organism":"Homo sapiens (Human)","status":"dark","length":304,"sequence":"MSLMVISMACVGFFWLQGAWPHEGFRRKPSLLAHPGRLVKSEETVILQCWSDVMFEHFLLHREGTFNDTLRLIGEHIDGVSKANFSIGRMRQDLAGTYRCYGSVPHSPYQFSAPSDPLDIVITGLYEKPSLSAQPGPTVLAGESVTLSCSSWSSYDMYHLSTEGEAHERRFSAGPKVNGTFQADFPLGPATQGGTYRCFGSFHDSPYEWSKSSDPLLVSVTGNPSNSWPSPTEPSSKTGNPRHLHVLIGTSVVKLPFTILLFFLLHRWCSDKKNASVMDQGPAGNRTVNREDSDEQDHQEVSYA","function_summary":"A cell-surface, single-pass immune receptor with tandem immunoglobulin-like domains that binds class I–like ligands to regulate leukocyte defense programs. Its extracellular beta-sandwich modules mediate high-affinity recognition at the plasma membrane, where ligand-induced clustering likely recruits membrane-proximal signaling machinery to tune cytotoxic and tolerance pathways characteristic of immune surveillance.","plain_language":"KIR2DS3 has barely been studied. The model's best guess: A cell-surface, single-pass immune receptor with tandem immunoglobulin-like domains that binds class I–like ligands to regulate leukocyte defense programs. Its extracellular beta-sandwich modules mediate high-affinity recognition at the plasma membrane, where ligand-induced clustering likely recruits membrane-proximal signaling machinery to tune cytotoxic and tolerance pathways characteristic of immune surveillance.","uniprot_summary":"Probable immunoglobulin-like receptor.","go_terms":{"molecular_function":[{"id":"GO:0005515","label":"protein binding"}],"biological_process":[{"id":"GO:0006968","label":"cellular defense response"}],"cellular_component":[{"id":"GO:0005886","label":"plasma membrane"}]},"interpro":[{"id":"IPR013783","name":"Immunoglobulin-like fold","type":"homologous_superfamily","start":22,"end":122},{"id":"IPR036179","name":"Immunoglobulin-like domain superfamily","type":"homologous_superfamily","start":27,"end":124},{"id":"IPR013783","name":"Immunoglobulin-like fold","type":"homologous_superfamily","start":125,"end":225},{"id":"IPR036179","name":"Immunoglobulin-like domain superfamily","type":"homologous_superfamily","start":126,"end":222},{"id":"IPR003599","name":"Immunoglobulin domain subtype","type":"domain","start":34,"end":123},{"id":"IPR013151","name":"Immunoglobulin-like beta-sandwich domain","type":"domain","start":38,"end":111},{"id":"IPR003599","name":"Immunoglobulin domain subtype","type":"domain","start":134,"end":221},{"id":"IPR013151","name":"Immunoglobulin-like beta-sandwich domain","type":"domain","start":136,"end":210},{"id":"IPR050412","name":"Immunoglobulin-like Receptors in Immune Regulation","type":"family","start":28,"end":264}],"reasoning":"I begin with the InterPro architecture. Two contiguous immunoglobulin-like regions dominate the ectodomain: an N-terminal Ig-like module annotated by IPR013783 (Immunoglobulin-like fold, residues 22–122) and IPR036179 (Immunoglobulin-like domain superfamily, residues 27–124), followed by a second Ig-like module annotated by IPR013783 (Immunoglobulin-like fold, residues 125–225) and IPR036179 (Immunoglobulin-like domain superfamily, residues 126–222). Within these superfamily envelopes, the N-terminal Ig unit is further specified by IPR003599 (Immunoglobulin domain subtype, residues 34–123) and IPR013151 (Immunoglobulin-like beta-sandwich domain, residues 38–111), while the C-terminal Ig unit is specified by IPR003599 (Immunoglobulin domain subtype, residues 134–221) and IPR013151 (Immunoglobulin-like beta-sandwich domain, residues 136–210). The overall family assignment IPR050412 (Immunoglobulin-like Receptors in Immune Regulation, residues 28–264) ties these tandem Ig domains to immune-receptor roles. This tandem Ig arrangement is characteristic of type I single-pass receptors that project two Ig-like domains extracellularly for ligand recognition.\n\nThis extracellular Ig scaffold dictates molecular function as protein binding (GO:0005515). The paired Ig-like beta-sandwich domains create a rigid, solvent-exposed surface optimized for binding cell-surface ligands—classically MHC class I or MHC class I–like molecules—through a mechanism that relies on shape complementarity and electrostatic contacts rather than catalysis. The absence of enzymatic motifs and the presence of receptor-family signatures reinforce a non-catalytic, ligand-binding role.\n\nFrom this binding capacity, the biological process follows. An Ig-like immune receptor that recognizes class I–like ligands initiates or modulates leukocyte behavior, aligning with cellular defense response (GO:0006968). Such receptors tune cytotoxic responses and innate-like lymphocyte pathways by triggering or restraining effector programs upon ligand engagement.\n\nThe cellular context is defined by the single-pass type I membrane topology and the Ig ectodomain. This architecture places the protein at the plasma membrane (GO:0005886), with an N-terminal extracellular region and a short cytoplasmic tail. The single-pass nature constrains it to the cell surface where it can survey neighboring cells and initiate signaling.\n\nMechanistically, the tandem Ig ectodomain binds class I–like ligands and stabilizes receptor clusters that couple to intracellular signaling machinery. Although the cytoplasmic motifs of this receptor class are diverse, immune-regulatory Ig-like receptors commonly signal via tyrosine-based motifs or membrane-proximal associations that recruit kinases and adaptors. I therefore hypothesize that this receptor forms ligand-induced complexes at the cell surface that modulate downstream pathways controlling cytotoxic lymphocyte activity and tolerance thresholds. Likely extracellular partners include class I–like molecules on target cells, while intracellular partners may include kinases and adaptors that assemble at the membrane-proximal tail to fine-tune defense responses.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-Q14952.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/Q14952"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/Q14952/entry","atlas":"/p/Q14952"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}