{"uniprot":"A6NLU5","gene":"VSTM2B","name":"V-set and transmembrane domain-containing protein 2B","organism":"Homo sapiens (Human)","status":"dark","length":285,"sequence":"MEQRNRLGALGYLPPLLLHALLLFVADAAFTEVPKDVTVREGDDIEMPCAFRASGATSYSLEIQWWYLKEPPRELLHELALSVPGARSKVTNKDATKISTVRVQGNDISHRLRLSAVRLQDEGVYECRVSDYSDDDTQEHKAQAMLRVLSRFAPPNMQAAEAVSHIQSSGPRRHGPASAANANNAGAASRTTSEPGRGDKSPPPGSPPAAIDPAVPEAAAASAAHTPTTTVAAAAAASSASPPSGQAVLLRQRHGSGTGRSYTTDPLLSLLLLALHKFLRLLLGH","function_summary":"A neuronal cell-surface adhesion/scaffold protein that presents an extracellular immunoglobulin V-set module on a single-pass type I membrane anchor to mediate multivalent protein binding. By forming adhesive complexes at the plasma membrane, it organizes and stabilizes synaptic junctions in neural tissue, likely by clustering at the cell surface and recruiting intracellular scaffolds through its short cytosolic tail to shape synapse architecture.","plain_language":"VSTM2B has barely been studied. The model's best guess: A neuronal cell-surface adhesion/scaffold protein that presents an extracellular immunoglobulin V-set module on a single-pass type I membrane anchor to mediate multivalent protein binding. By forming adhesive complexes at the plasma membrane, it organizes and stabilizes synaptic junctions in neural tissue, likely by clustering at the cell surface and recruiting intracellular scaffolds through its short cytosolic tail to shape synapse architecture.","uniprot_summary":"May be involved in synapse junction formation.","go_terms":{"molecular_function":[{"id":"GO:0005515","label":"protein binding"}],"biological_process":[{"id":"GO:0050808","label":"synapse organization"}],"cellular_component":[{"id":"GO:0005886","label":"plasma membrane"}]},"interpro":[{"id":"IPR036179","name":"Immunoglobulin-like domain superfamily","type":"homologous_superfamily","start":29,"end":150},{"id":"IPR013783","name":"Immunoglobulin-like fold","type":"homologous_superfamily","start":31,"end":161},{"id":"IPR007110","name":"Immunoglobulin-like domain","type":"domain","start":14,"end":143},{"id":"IPR013106","name":"Immunoglobulin V-set domain","type":"domain","start":33,"end":140},{"id":"IPR003599","name":"Immunoglobulin domain subtype","type":"domain","start":34,"end":149},{"id":"IPR051102","name":"Immunoglobulin superfamily V-set and transmembrane domain-containing protein","type":"family","start":21,"end":257}],"reasoning":"I begin with the InterPro architecture. The ectodomain is defined by a dense cluster of immunoglobulin signatures: IPR007110 (Immunoglobulin-like domain, residues 14–143) sits centrally and is encompassed by IPR036179 (Immunoglobulin-like domain superfamily, residues 29–150) and IPR013783 (Immunoglobulin-like fold, residues 31–161), indicating a canonical Ig-like beta-sandwich scaffold. Within this scaffold, IPR013106 (Immunoglobulin V-set domain, residues 33–140) and IPR003599 (Immunoglobulin domain subtype, residues 34–149) specify a V-set module optimized for extracellular adhesion and receptor recognition. The overall family assignment IPR051102 (Immunoglobulin superfamily V-set and transmembrane domain-containing protein, residues 21–257) ties this ectodomain to a single-pass type I membrane topology, implying an N-terminal signal peptide and luminal Ig domain followed by a transmembrane helix and a short cytosolic tail. This ordered layout—extracellular V-set Ig domain leading into a single-pass membrane anchor—creates a cell-surface adhesion/scaffold module that binds other proteins and organizes higher-order assemblies.\n\nThis Ig V-set architecture causes a molecular function centered on multivalent protein binding (GO:0005515). Ig-like ectodomains mediate homophilic and heterophilic interactions with other cell-surface molecules and extracellular matrix components; the absence of catalytic motifs and the presence of adhesive Ig modules argue that binding and scaffolding—not enzymatic chemistry—dominate function.\n\nFrom this binding capacity, the biological role follows. Ig superfamily single-pass receptors frequently pattern neural cell-surface codes that assemble synaptic specializations. The V-set domain provides adhesive specificity that nucleates and stabilizes synaptic junctions, aligning pre- and post-synaptic membranes and recruiting cytoskeletal and signaling complexes. This causal chain—extracellular adhesion via Ig V-set leading to synaptic junction assembly—maps to synapse organization (GO:0050808).\n\nCellular location is dictated by the topology and function. The IPR051102 family and the type I single-pass arrangement place the protein at the cell surface, consistent with a plasma membrane residence (GO:0005886). The extracellular Ig domain projects into the synaptic cleft, while the cytosolic tail can couple to intracellular adaptors that tune synaptic architecture.\n\nMechanistically, I hypothesize that the ectodomain forms cis- and trans-adhesive contacts that cluster the receptor into membrane microdomains. This clustering recruits intracellular scaffolds through the cytosolic tail to coordinate actin and membrane-associated assemblies that define synaptic junctions. Likely partners include other Ig-superfamily adhesion molecules and synaptic organizers at the neuronal surface and perisynaptic region, enabling precise alignment and maturation of synapses.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-A6NLU5.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/A6NLU5"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/A6NLU5/entry","atlas":"/p/A6NLU5"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}