{"uniprot":"Q5JSJ4","gene":"INTS6L","name":"Integrator complex subunit 6-like","organism":"Homo sapiens (Human)","status":"dark","length":898,"sequence":"MPILLFLIDTSASMNQRTDLGTSYLDIAKGAVELFLKLRARDPASRGDRYMLVTYDEPPYCIKAGWKENHATFMSELKNLQASGLTTLGQALRSSFDLLNLNRLISGIDNYGQGRNPFFLEPSILITITDGNKLTSTAGVQEELHLPLNSPLPGSELTKEPFRWDQRLFALVLRLPGVASTEPEQLGSVPTDESAITQMCEVTGGRSYCVRTQRMLNQCLESLVQKVQSGVVINFEKTGPDPLPIGEDGLMDSSRPSNSFAAQPWHSCHKLIYVRPNSKTGVPVGHWPIPESFWPDQNLPSLPPRTSHPVVRFSCVDCEPMVIDKLPFDKYELEPSPLTQYILERKSPHTCWQVFVTSSGKYNELGYPFGYLKASTTLTCVNLFVMPYNYPVLLPLLDDLFKVHKLKPNLKWRQAFDSYLKTLPPYYLLPLKKALRMMGAPNLISDNLDCGLSYSVISYLKKLSQQTKLESERILASVGKKPPQEIGIKVKNHSGGGMSLTHNKNFRKLLKEITGETALRLTELNTKEFAGFQIGLLNKDLKPQTYRNAYDIPRRGLLDQLTRMRSNLLKTHKFIVGQDEDSLHSVPVAQMGNYQEYLKTLASPLREIDPDQPKRLHTFGNPFKQDKKGMMIDEADEFVAGPQNKVKRPGEPNSPMSSKRRRSMSLLLRKPQTPPTVTNHVGGKGPPSASWFPSYPNLIKPTLVHTDATIIHDGHEEKMENGQITPDGFLSKSAPSELINMTGDLMPPNQVDSLSDDFTSLSKDGLIQKPGSNAFVGGAKNCSLSVDDQKDPVASTLGAMPNTLQITPAMAQGINADIKHQLMKEVRKFGRKYERIFILLEEVQGPLEMKKQFVEFTIKEAARFKRRVLIQYLEKVLEKINSHHLHNNISHINSRSSC","function_summary":"A large, soluble scaffold that assembles multiprotein complexes to regulate transcription and chromatin state. Its N-terminal interaction hub and central stabilizing core organize assemblies that recruit chromatin-modifying and RNA-processing factors, thereby promoting chromatin remodeling and RNA-directed heterochromatin formation. It operates predominantly in the nucleoplasm and also associates with actin-linked assemblies, consistent with a role in coupling nuclear architecture to transcriptional repression.","plain_language":"INTS6L has barely been studied. The model's best guess: A large, soluble scaffold that assembles multiprotein complexes to regulate transcription and chromatin state. Its N-terminal interaction hub and central stabilizing core organize assemblies that recruit chromatin-modifying and RNA-processing factors, thereby promoting chromatin remodeling and RNA-directed heterochromatin formation.","uniprot_summary":"May be involved in transcriptional regulation.","go_terms":{"molecular_function":[{"id":"GO:0005515","label":"protein binding"}],"biological_process":[{"id":"GO:0006338","label":"chromatin remodeling"},{"id":"GO:0031048","label":"RNA-mediated heterochromatin formation"}],"cellular_component":[{"id":"GO:0005654","label":"nucleoplasm"},{"id":"GO:0015629","label":"actin cytoskeleton"}]},"interpro":[{"id":"IPR036465","name":"von Willebrand factor A-like domain superfamily","type":"homologous_superfamily","start":4,"end":225},{"id":"IPR002035","name":"von Willebrand factor, type A","type":"domain","start":3,"end":227},{"id":"IPR057413","name":"Integrator complex subunit 6-like, beta-barrel domain","type":"domain","start":263,"end":402},{"id":"IPR029307","name":"INTS6/SAGE1/DDX26B/CT45, C-terminal","type":"domain","start":814,"end":875},{"id":"IPR051113","name":"Integrator complex subunit 6","type":"family","start":1,"end":885}],"reasoning":"I begin with the domain architecture. The N-terminus carries IPR002035 (von Willebrand factor, type A domain, residues 3–227), embedded within IPR036465 (von Willebrand factor A-like domain superfamily, residues 4–225). VWA modules form Rossmann-like β-sheet scaffolds that mediate high-affinity macromolecular contacts and often nucleate assembly of large complexes. This N-terminal VWA platform is followed by IPR057413 (Integrator complex subunit 6-like, beta-barrel domain, residues 263–402), a structural core that typically stabilizes higher-order assemblies and provides additional protein–protein interfaces. The C-terminus contains IPR029307 (INTS6/SAGE1/DDX26B/CT45, C-terminal, residues 814–875), a conserved tail that frequently tunes partner specificity and complex integrity. The entire polypeptide is encompassed by IPR051113 (Integrator complex subunit 6 family, residues 1–885), which defines a scaffold specialized for assembling Integrator-like assemblies. This ordered layout—an N-terminal VWA interaction hub, a central β-barrel stabilizer, and a conserved C-terminal determinant—causes a multivalent, non-enzymatic scaffold optimized for GO:0005515 protein binding as the primary molecular function.\n\nFrom this scaffolded binding capacity, I infer roles in chromatin-centered pathways. The Integrator-complex lineage and the VWA-driven assembly logic are well-suited to recruit chromatin regulators and RNA-processing factors that enforce transcriptional repression. Such assemblies naturally drive GO:0006338 chromatin remodeling by positioning nucleosome-modifying activities and by stabilizing repressive complexes. The same architecture can channel small-RNA-guided pathways toward condensed chromatin, supporting GO:0031048 RNA-mediated heterochromatin formation. Together, these processes explain how a non-catalytic scaffold can steer both nucleosome landscape control and RNA-directed silencing.\n\nCellular localization follows from function and architecture. The absence of transmembrane features and the presence of complex-assembly domains point to a soluble nuclear scaffold. This supports residence in the GO:0005654 nucleoplasm, where chromatin remodeling and heterochromatin assembly occur. A second localization cue arises from the actin-associated machinery: nuclear actin and actin-regulatory complexes participate in chromatin organization and RNA processing. The β-barrel and C-terminal modules can anchor to actin-linked assemblies, rationalizing association with the GO:0015629 actin cytoskeleton and explaining observed cytoplasmic/nuclear distribution.\n\nMechanistically, I hypothesize that the N-terminal VWA domain nucleates a core complex that captures Integrator-like partners and chromatin silencers; the central β-barrel stabilizes higher-order oligomers; and the C-terminal module selects pathway-specific partners. This tri-partite scaffold likely recruits histone-modifying enzymes and small-RNA effectors to deposit or maintain heterochromatin, while coupling to nuclear actin to shape chromatin topology. Predicted interaction partners include Integrator subunits and chromatin modifiers that together enforce transcriptional repression and coordinate RNA processing with chromatin state.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-Q5JSJ4.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/Q5JSJ4"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/Q5JSJ4/entry","atlas":"/p/Q5JSJ4"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}