{"uniprot":"P0C6S8","gene":"LINGO3","name":"Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 3","organism":"Homo sapiens (Human)","status":"dark","length":592,"sequence":"MTCWLCVLSLPLLLLPAAPPPAGGCPARCECTVQTRAVACTRRRLTAVPDGIPAETRLLELSRNRIRCLNPGDLAALPALEELDLSENAIAHVEPGAFANLPRLRVLRLRGNQLKLIPPGVFTRLDNLTLLDLSENKLVILLDYTFQDLHSLRRLEVGDNDLVFVSRRAFAGLLALEELTLERCNLTALSGESLGHLRSLGALRLRHLAIASLEDQNFRRLPGLLHLEIDNWPLLEEVAAGSLRGLNLTSLSVTHTNITAVPAAALRHQAHLTCLNLSHNPISTVPRGSFRDLVRLRELHLAGALLAVVEPQAFLGLRQIRLLNLSNNLLSTLEESTFHSVNTLETLRVDGNPLACDCRLLWIVQRRKTLNFDGRLPACATPAEVRGDALRNLPDSVLFEYFVCRKPKIRERRLQRVTATAGEDVRFLCRAEGEPAPTVAWVTPQHRPVTATSAGRARVLPGGTLEIQDARPQDSGTYTCVASNAGGNDTYFATLTVRPEPAANRTPGEAHNETLAALRAPLDLTTILVSTAMGCITFLGVVLFCFVLLFVWSRGRGQHKNNFSVEYSFRKVDGPAAAAGQGGARKFNMKMI","function_summary":"A membrane-anchored extracellular adhesion receptor that uses a leucine-rich repeat scaffold capped by a cysteine-rich segment and followed by an immunoglobulin-like domain to mediate high-specificity protein binding at the cell surface. By assembling and stabilizing multiprotein complexes, it promotes the formation and maturation of synaptic junctions at the plasma membrane, where its modular ectodomain organizes presynaptic and postsynaptic machinery to drive synapse assembly.","plain_language":"LINGO3 has barely been studied. The model's best guess: A membrane-anchored extracellular adhesion receptor that uses a leucine-rich repeat scaffold capped by a cysteine-rich segment and followed by an immunoglobulin-like domain to mediate high-specificity protein binding at the cell surface. By assembling and stabilizing multiprotein complexes, it promotes the formation and maturation of synaptic junctions at the plasma membrane, where its modular ectodomain organizes presynaptic and postsynaptic machinery to drive synapse assembly.","uniprot_summary":"Involved in synapse assembly.","go_terms":{"molecular_function":[{"id":"GO:0005515","label":"protein binding"}],"biological_process":[{"id":"GO:0051965","label":"positive regulation of synapse assembly"}],"cellular_component":[{"id":"GO:0005886","label":"plasma membrane"}]},"interpro":[{"id":"IPR032675","name":"Leucine-rich repeat domain superfamily","type":"homologous_superfamily","start":37,"end":402},{"id":"IPR013783","name":"Immunoglobulin-like fold","type":"homologous_superfamily","start":403,"end":500},{"id":"IPR036179","name":"Immunoglobulin-like domain superfamily","type":"homologous_superfamily","start":403,"end":501},{"id":"IPR000372","name":"Leucine-rich repeat N-terminal domain","type":"domain","start":24,"end":58},{"id":"IPR000483","name":"Cysteine-rich flanking region, C-terminal","type":"domain","start":352,"end":405},{"id":"IPR007110","name":"Immunoglobulin-like domain","type":"domain","start":407,"end":496},{"id":"IPR013098","name":"Immunoglobulin I-set","type":"domain","start":412,"end":497},{"id":"IPR003599","name":"Immunoglobulin domain subtype","type":"domain","start":414,"end":498},{"id":"IPR003598","name":"Immunoglobulin subtype 2","type":"domain","start":420,"end":487},{"id":"IPR050541","name":"Leucine-rich repeat and transmembrane domain-containing protein","type":"family","start":158,"end":505},{"id":"IPR003591","name":"Leucine-rich repeat, typical subtype","type":"repeat","start":77,"end":100},{"id":"IPR001611","name":"Leucine-rich repeat","type":"repeat","start":80,"end":101},{"id":"IPR003591","name":"Leucine-rich repeat, typical subtype","type":"repeat","start":101,"end":124},{"id":"IPR001611","name":"Leucine-rich repeat","type":"repeat","start":102,"end":162},{"id":"IPR003591","name":"Leucine-rich repeat, typical subtype","type":"repeat","start":125,"end":148},{"id":"IPR003591","name":"Leucine-rich repeat, typical subtype","type":"repeat","start":149,"end":172},{"id":"IPR003591","name":"Leucine-rich repeat, typical subtype","type":"repeat","start":173,"end":196},{"id":"IPR001611","name":"Leucine-rich repeat","type":"repeat","start":247,"end":303},{"id":"IPR003591","name":"Leucine-rich repeat, typical subtype","type":"repeat","start":247,"end":268},{"id":"IPR003591","name":"Leucine-rich repeat, typical subtype","type":"repeat","start":270,"end":292},{"id":"IPR003591","name":"Leucine-rich repeat, typical subtype","type":"repeat","start":293,"end":316},{"id":"IPR003591","name":"Leucine-rich repeat, typical subtype","type":"repeat","start":317,"end":340},{"id":"IPR001611","name":"Leucine-rich repeat","type":"repeat","start":319,"end":340}],"reasoning":"I begin by dissecting the domain architecture. The N-terminus carries IPR000372 (Leucine-rich repeat N-terminal domain, residues 24–58), which caps an extended LRR scaffold defined by IPR032675 (Leucine-rich repeat domain superfamily, residues 37–402). This LRR core is punctuated by multiple IPR003591/IRP001611 leucine-rich repeat units—typical subtypes spanning residues 77–100, 80–101, 101–124, 102–162, 125–148, 149–172, 173–196, and a mid-region cluster at 247–340—culminating in IPR000483 (Cysteine-rich flanking region, C-terminal, residues 352–405). This canonical LRRNT–LRR array–LRRCT arrangement creates a curved solenoid surface optimized for avid, shape-complementary protein binding. Immediately C-terminal to the LRR block lies an immunoglobulin module: IPR013783 (Immunoglobulin-like fold, residues 403–500), IPR036179 (Immunoglobulin-like domain superfamily, residues 403–501), IPR007110 (Immunoglobulin-like domain, residues 407–496), and IPR013098/IPR003599/IPR003598 (Ig I-set and subtype annotations, residues 412–497/414–498/420–487). The juxtaposition of an LRR solenoid with an Ig-like module is a hallmark of cell-adhesion and synaptic adhesion receptors that mediate high-specificity extracellular interactions. The overall architecture is captured by IPR050541 (Leucine-rich repeat and transmembrane domain-containing protein family, residues 158–505), which, despite its generic transmembrane annotation, here supports a membrane-anchored extracellular adhesion receptor.\n\nThis architecture dictates molecular function. The LRRNT cap and cysteine-rich C-terminal flanking region stabilize a concave LRR surface that binds partner proteins with high affinity and selectivity, while the Ig-like domain provides an additional adhesive interface and rigidity. Together, these modules cause robust multivalent protein binding, aligning with GO:0005515 protein binding as the operative molecular function.\n\nFrom function to process, an extracellular LRR–Ig adhesion receptor at the cell surface is primed to organize synaptic contacts. The LRR solenoid commonly nucleates assembly of presynaptic and postsynaptic complexes, and the Ig-like domain refines specificity and spacing—mechanistically promoting the formation and stabilization of synaptic junctions. This causal chain supports GO:0051965 positive regulation of synapse assembly.\n\nCellular location follows directly. The presence of a membrane-anchored extracellular LRR–Ig ectodomain and the family signature of membrane-associated LRR proteins place the protein at the cell surface. This supports a plasma membrane residence consistent with GO:0005886 plasma membrane and the stated membrane localization.\n\nMechanistically, I hypothesize that the LRR array forms the principal ligand-binding platform that captures extracellular synaptic organizers, while the Ig-like domain stabilizes the complex and tunes intermembrane spacing. Likely partners include presynaptic organizers and postsynaptic adhesion systems that recognize LRR–Ig ectodomains. Candidate interactors include neurexins and neuroligins for trans-synaptic alignment, cerebellin–GluD complexes for inhibitory synapse specification, and receptor phosphatases such as LAR family members that couple adhesion to cytoskeletal remodeling. Through these assemblies, the receptor concentrates and stabilizes synaptic components at the plasma membrane, driving synapse assembly and maturation.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-P0C6S8.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/P0C6S8"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/P0C6S8/entry","atlas":"/p/P0C6S8"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}