{"uniprot":"A6NCI4","gene":"VWA3A","name":"von Willebrand factor A domain-containing protein 3A","organism":"Homo sapiens (Human)","status":"dark","length":1184,"sequence":"MKKYRKISIGCFAMATQTSHVFHGQENMFLENHCIRRNTGRDSKKPLKQKNMNGLGQNSDNGLLVTHVNQTQDLLRLQGSETQSSDWEDSEDWLSAHSLKCQKLTLADLISQGTEVLEEGTNVVQKICFSTQIIRHFESKLSDTIEVYQERIQWLTENSKKAFGLIKGARVSILIDVSAISSGPQKEEFQKDLMSLIDEQLSHKEKLFVLSFGTNAGSLWPDPMEVSASTLQELKLWVKTLQPDGGSNLLQALKKIFTLKGLDSLVAIMRSCPDQPSEILSDYIQQSTMGRDLIIHFITYRCDDQMPPAVLKNLAEAVRGYYHCYSPKMEHYTSRDMDELLAEIQKAQSLLSHVQALQHSSPCEALTCTMEEISTEITNGPLISLLPKPPKHDAPLTIEFPNLDKTSAEWLKVNGLKAKKLSLYQVLAPNAFSPVEEFVPILQKTVSSTIHEKAMIQFEWHDGTVKNIHVDPPFLYKYQQQLSRAMRMYERRIEWLSLASRRIWGTVCEKRVVVLLDISATNSMYIIHIQHSLRLLLEEQLSNKDCFNLIAFGSTIESWRPEMVPVSHNNLQSAWRWALNLRCRGSRNVLSALRKAVEVDFKDKDKHQSQGIYLFTGGIPDQDMPTLSAYMAEACGGCDLQLNVCLFYVGEPKMDTTPPARYASHTDTAAAYKEVTRAAGGRFHWFGDTGIYESDDINSIMSEMEKALNYSQKCAFLMASLKNHSGKVLGSSALPKEKPKTLQLRSQPKKLCPPRPTVPLGARMSIKDDPDREKSPPLKSLKWRPLSSRVGISPAAAQPTKEGMMELRRKTKSREAETSLLLFYTEKGNDVGSVYKKYPQGRGLRRTSSSIDLPRKDTVCSSQEWVAKYGLKKLKLEISRCMGPNCTHQKSGQRSASAKHCSIFPSVEIHGVVRHIQWTPREMEVYIRHLEKVLRRYVQRLQWLLSGSRRLFGTVLESKVCILLDTSGSMGPYLQQVKTELVLLIWEQLRKCCDSFNLLSFAESFQSWQDTLVETTDAACHEAMQWVTHLQAQGSTSILQALLKAFSFHDLEGLYLLTDGKPDTSCSLVLNEVQKLREKRDVKVHTISLNCSDRAAVEFLRKLASFTGGRYHCPVGEDTLSKIHSLLTKGFINEKDPTLPPFEGDDLRILAQEITKARSFLWQAQSFRSQLQKKNDAEPKVTLS","function_summary":"A soluble, multivalent scaffold that uses three von Willebrand A-like modules to assemble and stabilize macromolecular complexes controlling cell-cycle transitions and genome maintenance. By concentrating checkpoint and repair assemblies in the nucleus and dynamically exchanging with the cytosol, it coordinates pathways that ensure proper progression through mitosis and supports DNA repair and damage checkpoint signaling.","plain_language":"VWA3A has barely been studied. The model's best guess: A soluble, multivalent scaffold that uses three von Willebrand A-like modules to assemble and stabilize macromolecular complexes controlling cell-cycle transitions and genome maintenance. By concentrating checkpoint and repair assemblies in the nucleus and dynamically exchanging with the cytosol, it coordinates pathways that ensure proper progression through mitosis and supports DNA repair and damage checkpoint signaling.","uniprot_summary":"Plays a role in cell cycle control.","go_terms":{"molecular_function":[{"id":"GO:0005515","label":"protein binding"}],"biological_process":[{"id":"GO:0006281","label":"DNA repair"}],"cellular_component":[{"id":"GO:0005829","label":"cytosol"},{"id":"GO:0005654","label":"nucleoplasm"}]},"interpro":[{"id":"IPR036465","name":"von Willebrand factor A-like domain superfamily","type":"homologous_superfamily","start":167,"end":328},{"id":"IPR036465","name":"von Willebrand factor A-like domain superfamily","type":"homologous_superfamily","start":507,"end":705},{"id":"IPR036465","name":"von Willebrand factor A-like domain superfamily","type":"homologous_superfamily","start":957,"end":1132},{"id":"IPR002035","name":"von Willebrand factor, type A","type":"domain","start":170,"end":324},{"id":"IPR002035","name":"von Willebrand factor, type A","type":"domain","start":511,"end":635},{"id":"IPR002035","name":"von Willebrand factor, type A","type":"domain","start":957,"end":1131}],"reasoning":"I begin with the InterPro architecture. Three tandem von Willebrand factor A-like modules are evident: IPR036465 (von Willebrand factor A-like domain superfamily) spans residues 167–328, 507–705, and 957–1132, and these superfamily envelopes contain three specific vWA domains—IPR002035 (von Willebrand factor, type A domain) at residues 170–324, 511–635, and 957–1131. The ordered layout—N-terminal vWA (170–324), central vWA (511–635), and C-terminal vWA (957–1131)—creates a tri-modular scaffold. vWA domains are non-catalytic adhesion modules that mediate high-affinity macromolecular contacts through metal-coordination and surface grooves; their repetition expands binding valency and specificity. This architecture causally enforces multivalent protein binding, aligning with GO:0005515 protein binding as the primary molecular function.\n\nFrom this binding-centric core, I infer how the protein operates in cell-cycle control. vWA arrays commonly assemble transient complexes rather than catalyze reactions. In the nucleus, such scaffolds can coordinate checkpoint and repair assemblies. The presence of multiple vWA modules supports a role in assembling and stabilizing complexes that govern DNA damage checkpoints and repair focus formation. This scaffolding logic naturally feeds into genome maintenance pathways, supporting the biological process formalized as GO:0006281 DNA repair.\n\nCellular localization follows from function and architecture. The absence of transmembrane segments and the reliance on interaction modules indicate a soluble macromolecule that shuttles between compartments. Its operational context in checkpoint and repair assemblies places it in the GO:0005654 nucleoplasm, where DNA damage signaling and repair complexes form. Dynamic pools in the GO:0005829 cytosol are consistent with regulated nucleo-cytoplasmic trafficking and assembly/disassembly cycles typical of cell-cycle control factors.\n\nMechanistically, the tri-vWA scaffold likely times and stabilizes assemblies that couple DNA replication and mitotic entry. By concentrating checkpoint mediators and repair factors in the nucleoplasm, it can enforce proper cell-cycle progression and ensure that DNA lesions are resolved before mitosis. I hypothesize that it binds and coordinates nuclear substrates such as cyclin-dependent kinase complexes and checkpoint mediators, using its vWA surfaces to recruit and position repair and checkpoint modules. This predicts transient interactions with nuclear transport and cell-cycle regulators that tune its nucleoplasmic residence and cytosolic shuttling.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-A6NCI4.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/A6NCI4"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/A6NCI4/entry","atlas":"/p/A6NCI4"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}