{"uniprot":"P69849","gene":"NOMO3","name":"Nodal modulator 3","organism":"Homo sapiens (Human)","status":"dark","length":1222,"sequence":"MLVGQGAGPLGPAVVTAAVVLLLSGVGPAHGSEDIVVGCGGFVKSDVEINYSLIEIKLYTKHGTLKYQTDCAPNNGYFMIPLYDKGDFILKIEPPLGWSFEPTTVELHVDGVSDICTKGGDINFVFTGFSVNGKVLSKGQPLGPAGVQVSLRNTGTEAKIQSTVTQPGGKFAFFKVLPGDYEILATHPTWALKEASTTVRVTNSNANAASPLIVAGYNVSGSVRSDGEPMKGVKFLLFSSLVTKEDVLGCNVSPVPGFQPQDESLVYLCYTVSREDGSFSFYSLPSGGYTVIPFYRGERITFDVAPSRLDFTVEHDSLKIEPVFHVMGFSVTGRVLNGPEGDGVPEAVVTLNNQIKVKTKADGSFRLENITTGTYTIHAQKEHLYFETVTIKIAPNTPQLADIVATGFSVCGQISIIRFPDTVKQMNKYKVVLSSQDKDKSLVTVETDAHGSFCFKANPGTYKVQVMVPEAETRAGLTLKPQTFPLTVTDRPVMDVAFVQFLASVSGKVSCLDTCGDLLVTLQSLSRQGEKRSLQLSGKVNAMTFTFDNVLPGKYKISIMHEDWCWKNKSLEVEVLEDDVSAVEFRQTGYMLRCSLSHAITLEFYQDGNGRENVGIYNLSKGVNRFCLSKPGVYKVTPRSCHRFEQAFYTYDTSSPSILTLTAIRHHVLGTITTDKMMDVTVTIKSSIDSEPALVLGPLKSVQELRREQQLAEIEARRQEREKNGNEEGEERMTKPPVQEMVDELQGPFSYDFSYWARSGEKITVTPSSKELLFYPPSMEAVVSGESCPGKLIEIHGKAGLFLEGQIHPELEGVEIVISEKGASSPLITVFTDDKGAYSVGPLHSDLEYTVTSQKEGYVLTAVEGTIGDFKAYALAGVSFEIKAEDDQPLPGVLLSLSGGLFRSNLLTQDNGILTFSNLSPGQYYFKPMMKEFRFEPSSQMIEVQEGQNLKITITGYRTAYSCYGTVSSLNGEPEQGVAMEAVGQNDCSIYGEDTVTDEEGKFRLRGLLPGCVYHVQLKAEGNDHIERALPHHRVIEVGNNDIDDVNIIVFRQINQFDLSGNVITSSEYLPTLWVKLYKSENLDNPIQTVSLGQSLFFHFPPLLRDGENYVVLLDSTLPRSQYDYILPQVSFTAVGYHKHITLIFNPTRKLPEQDIAQGSYIALPLTLLVLLAGYNHDKLIPLLLQLTSRLQGVGALGQAASDNSGPEDAKRQAKKQKTRRT","function_summary":"A large, secreted and membrane-proximal scaffold that assembles multiple beta-sandwich and transthyretin-like modules to create high-avidity binding surfaces. By organizing extracellular and membrane-associated complexes, it modulates developmental signaling circuits and likely dampens Notch pathway activity. Its multivalent architecture supports broad protein interactions and transient ribosome association near the cell surface, coupling co-translational handling of secretory clients to the attenuation of receptor–ligand signaling.","plain_language":"NOMO3 has barely been studied. The model's best guess: A large, secreted and membrane-proximal scaffold that assembles multiple beta-sandwich and transthyretin-like modules to create high-avidity binding surfaces. By organizing extracellular and membrane-associated complexes, it modulates developmental signaling circuits and likely dampens Notch pathway activity.","uniprot_summary":"May be involved in developmental processes. May act as a negative regulator of Notch signaling pathway.","go_terms":{"molecular_function":[{"id":"GO:0005515","label":"protein binding"},{"id":"GO:0043022","label":"ribosome binding"}],"biological_process":[{"id":"GO:0045746","label":"negative regulation of Notch signaling pathway"}],"cellular_component":[{"id":"GO:0016020","label":"membrane"}]},"interpro":[{"id":"IPR013783","name":"Immunoglobulin-like fold","type":"homologous_superfamily","start":122,"end":226},{"id":"IPR013784","name":"Carbohydrate-binding-like fold","type":"homologous_superfamily","start":127,"end":202},{"id":"IPR013784","name":"Carbohydrate-binding-like fold","type":"homologous_superfamily","start":329,"end":403},{"id":"IPR013784","name":"Carbohydrate-binding-like fold","type":"homologous_superfamily","start":883,"end":954},{"id":"IPR008969","name":"Carboxypeptidase-like, regulatory domain superfamily","type":"homologous_superfamily","start":964,"end":1053},{"id":"IPR055075","name":"NOMO-like, N-terminal beta-sandwich domain","type":"domain","start":40,"end":124},{"id":"IPR056189","name":"NOMO, third transthyretin-like domain","type":"domain","start":226,"end":325},{"id":"IPR056190","name":"NOMO, fifth transthyretin-like domain","type":"domain","start":409,"end":498},{"id":"IPR056319","name":"NOMO, seventh transthyretin-like domain","type":"domain","start":592,"end":664},{"id":"IPR056187","name":"NOMO, eighth prealbumin-like domain","type":"domain","start":746,"end":798},{"id":"IPR055073","name":"NOMO-like, ninth beta-sandwich domain","type":"domain","start":799,"end":873},{"id":"IPR041033","name":"SpaA-like, prealbumin fold domain subgroup 1","type":"domain","start":874,"end":955},{"id":"IPR056191","name":"NOMO, C-terminal transthyretin-like domain","type":"domain","start":1054,"end":1147},{"id":"IPR051417","name":"Serine-Aspartate Repeat-Containing","type":"family","start":44,"end":1191}],"reasoning":"I begin by dissecting the InterPro architecture and its order along the polypeptide. The N-terminus carries IPR055075 (NOMO-like, N-terminal beta-sandwich domain, residues 40–124), immediately followed by an extensive beta-sandwich/Ig-like core: IPR013783 (Immunoglobulin-like fold, residues 122–226) overlaps this region and continues into IPR056189 (NOMO, third transthyretin-like domain, residues 226–325). Mid-chain, there is a second transthyretin/prealbumin-like block: IPR013784 (Carbohydrate-binding-like fold, residues 127–202) overlaps the N-terminal Ig-like region and reinforces a beta-sandwich scaffold; a later carbohydrate-binding-like module appears again (IPR013784, residues 329–403), and this is followed by IPR056190 (NOMO, fifth transthyretin-like domain, residues 409–498). The central-to-distal region continues a series of NOMO-specific transthyretin/prealbumin-like domains—IPR056319 (NOMO, seventh transthyretin-like domain, residues 592–664), IPR056187 (NOMO, eighth prealbumin-like domain, residues 746–798), and IPR055073 (NOMO-like, ninth beta-sandwich domain, residues 799–873)—culminating in a C-terminal module that is characteristic of secreted beta-sandwich proteins: IPR041033 (SpaA-like, prealbumin fold domain subgroup 1, residues 874–955) and IPR013784 (Carbohydrate-binding-like fold, residues 883–954). Immediately downstream sits IPR008969 (Carboxypeptidase-like, regulatory domain superfamily, residues 964–1053), a non-catalytic regulatory fold often used for ligand or partner recognition. The extreme C-terminus is completed by IPR056191 (NOMO, C-terminal transthyretin-like domain, residues 1054–1147). The entire chain is encompassed by IPR051417 (Serine-Aspartate Repeat-Containing family, residues 44–1191), indicating an extended repeat-rich scaffold that favors multivalent binding.\n\nThis ordered array of beta-sandwich and transthyretin/prealbumin-like domains creates a modular, secreted scaffold optimized for avid, multivalent interactions rather than catalysis. The repeated NOMO/transthyretin-like modules and Ig-like fold collectively generate broad protein-binding surfaces, directly supporting GO:0005515 protein binding as a core molecular function. The presence of ribosome-engaging beta-sandwich modules and the overall secretory/surface-exposed architecture rationalize GO:0043022 ribosome binding: secreted and membrane-proximal scaffolds can transiently associate with ribosomes at the ER or cell surface to coordinate translation-coupled secretion and to chaperone client proteins.\n\nFrom these binding capabilities, I infer a role in signaling modulation. The multivalent scaffold can sequester or present ligands and receptors, thereby tuning pathway flux. This architecture naturally explains negative control of a juxtacrine signaling axis: by binding and stabilizing extracellular or membrane-proximal complexes, the protein can dampen receptor–ligand signaling throughput. This causal chain—multivalent binding scaffold leading to pathway attenuation—maps to GO:0045746 negative regulation of Notch signaling pathway.\n\nCellular placement follows from both the modular extracellular fold suite and the membrane-proximal annotation. The prealbumin/transthyretin-like and SpaA-like domains are archetypal extracellular folds, and the overall signal-sculpting role requires exposure near the cell surface. Thus, the protein operates at the membrane interface, consistent with GO:0016020 membrane, and aligns with a cell-membrane-associated, secreted/peripheral localization.\n\nMechanistically, I hypothesize that the tandem NOMO-like domains assemble a high-avidity platform that captures cell-surface complexes involved in developmental signaling. By clustering and stabilizing extracellular assemblies, the scaffold attenuates Notch pathway activation—likely by constraining receptor–ligand encounter geometry or by recruiting inhibitory partners. Its ribosome-binding propensity suggests coupling to ER-associated ribosomes, coordinating co-translational folding and secretion of pathway components. Likely interaction partners include membrane-proximal signaling modules and ribosome-associated factors that together tune Notch pathway output and developmental decisions.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-P69849.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/P69849"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/P69849/entry","atlas":"/p/P69849"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}