{"uniprot":"Q6ZTA4","gene":"TRIM67","name":"Tripartite motif-containing protein 67","organism":"Homo sapiens (Human)","status":"dark","length":783,"sequence":"MEEELKCPVCGSLFREPIILPCSHNVCLPCARTIAVQTPDGEQHLPQPLLLSRGSGLQAGAAAAASLEHDAAAGPACGGAGGSAAGGLGGGAGGGGDHADKLSLYSETDSGYGSYTPSLKSPNGVRVLPMVPAPPGSSAAAARGAACSSLSSSSSSITCPQCHRSASLDHRGLRGFQRNRLLEAIVQRYQQGRGAVPGTSAAAAVAICQLCDRTPPEPAATLCEQCDVLYCSACQLKCHPSRGPFAKHRLVQPPPPPPPPAEAASGPTGTAQGAPSGGGGCKSPGGAGAGATGGSTARKFPTCPEHEMENYSMYCVSCRTPVCYLCLEEGRHAKHEVKPLGAMWKQHKAQLSQALNGVSDKAKEAKEFLVQLKNILQQIQENGLDYEACLVAQCDALVDALTRQKAKLLTKVTKEREHKLKMVWDQINHCTLKLRQSTGLMEYCLEVIKENDPSGFLQISDALIKRVQVSQEQWVKGALEPKVSAEFDLTLDSEPLLQAIHQLDFIQMKCRVPPVPLLQLEKCCTRNNSVTLAWRMPPFTHSPVDGYILELDDGAGGQFREVYVGKETLCTIDGLHFNSTYNARVKAFNSSGVGPYSKTVVLQTSDVAWFTFDPNSGHRDIILSNDNQTATCSSYDDRVVLGTAAFSKGVHYWELHVDRYDNHPDPAFGVARASVVKDMMLGKDDKAWAMYVDNNRSWFMHCNSHTNRTEGGVCKGATVGVLLDLNKHTLTFFINGQQQGPTAFSHVDGVFMPALSLNRNVQVTLHTGLEVPTNLGRPKLSGN","function_summary":"A cytosolic E3 ubiquitin ligase that assembles a TRIM-like catalytic and recognition platform to regulate protein turnover and signaling. An N-terminal catalytic module drives ubiquitin transfer, while tandem B-box and C-terminal regions organize higher-order assemblies and a COS motif biases association with cytosolic structures. A C-terminal β-sandwich platform comprising fibronectin type III and SPRY domains provides multivalent substrate recognition. This architecture enables robust protein binding and self-directed autoubiquitination, positioning the enzyme to modulate cytoskeletal and membrane-proximal pathways from the cytosol.","plain_language":"TRIM67 has barely been studied. The model's best guess: A cytosolic E3 ubiquitin ligase that assembles a TRIM-like catalytic and recognition platform to regulate protein turnover and signaling. An N-terminal catalytic module drives ubiquitin transfer, while tandem B-box and C-terminal regions organize higher-order assemblies and a COS motif biases association with cytosolic structures.","uniprot_summary":"May possess E3 ubiquitin-protein ligase activity.","go_terms":{"molecular_function":[{"id":"GO:0005515","label":"protein binding"}],"biological_process":[{"id":"GO:0051865","label":"protein autoubiquitination"}],"cellular_component":[{"id":"GO:0005829","label":"cytosol"}]},"interpro":[{"id":"IPR013083","name":"Zinc finger, RING/FYVE/PHD-type","type":"homologous_superfamily","start":1,"end":60},{"id":"IPR013783","name":"Immunoglobulin-like fold","type":"homologous_superfamily","start":507,"end":607},{"id":"IPR036116","name":"Fibronectin type III superfamily","type":"homologous_superfamily","start":512,"end":605},{"id":"IPR013320","name":"Concanavalin A-like lectin/glucanase domain superfamily","type":"homologous_superfamily","start":576,"end":772},{"id":"IPR043136","name":"B30.2/SPRY domain superfamily","type":"homologous_superfamily","start":612,"end":767},{"id":"IPR001841","name":"Zinc finger, RING-type","type":"domain","start":7,"end":162},{"id":"IPR000315","name":"B-box-type zinc finger","type":"domain","start":203,"end":253},{"id":"IPR000315","name":"B-box-type zinc finger","type":"domain","start":298,"end":340},{"id":"IPR003649","name":"B-box, C-terminal","type":"domain","start":347,"end":473},{"id":"IPR017903","name":"COS domain","type":"domain","start":448,"end":506},{"id":"IPR003961","name":"Fibronectin type III","type":"domain","start":513,"end":607},{"id":"IPR001870","name":"B30.2/SPRY domain","type":"domain","start":589,"end":780},{"id":"IPR003877","name":"SPRY domain","type":"domain","start":648,"end":769},{"id":"IPR050617","name":"E3 ubiquitin-protein ligases and FN3/SPRY domain-containing proteins","type":"family","start":3,"end":773},{"id":"IPR017907","name":"Zinc finger, RING-type, conserved site","type":"conserved_site","start":22,"end":31}],"reasoning":"I begin by dissecting the InterPro architecture and its order along the polypeptide. The N-terminus (residues 1–60) carries IPR013083 (Zinc finger, RING/FYVE/PHD-type homologous superfamily), within which a catalytic IPR001841 RING-type zinc finger spans residues 7–162 and is reinforced by a conserved RING motif at residues 22–31 (IPR017907). This N-terminal RING module is the catalytic core that recruits E2 ubiquitin-conjugating enzymes and catalyzes ubiquitin transfer. Immediately downstream, the tripartite motif continues with two B-boxes and a B-box C-terminal region: IPR000315 (B-box-type zinc finger, residues 203–253) and IPR000315 (B-box-type zinc finger, residues 298–340) followed by IPR003649 (B-box, C-terminal, residues 347–473). This RING–B-box–B-box–C-terminal module is the canonical TRIM scaffold that enforces higher-order assembly and substrate selection. The mid-region contains IPR017903 (COS domain, residues 448–506), a cytoskeleton- and organelle-association module that biases localization toward cytosolic structures and supports cytoskeletal coupling.\n\nThe C-terminal half transitions into a β-sandwich recognition platform. Residues 507–607 form an Ig-like β-sandwich (IPR013783, Ig-like fold) that coincides with a fibronectin type III module (IPR003961, Fibronectin type III, residues 513–607; and IPR036116, FN3 superfamily, residues 512–605). This FN3/Ig-like scaffold frequently serves as a rigid spacer and substrate-binding surface. The extreme C-terminus is dominated by SPRY/B30.2 modules: IPR043136 (B30.2/SPRY domain superfamily, residues 612–767), IPR001870 (B30.2/SPRY domain, residues 589–780), and IPR003877 (SPRY domain, residues 648–769). These β-sandwich domains specialize in protein–protein recognition and target recruitment. The broader C-terminal region also maps to IPR013320 (Concanavalin A-like lectin/glucanase domain superfamily, residues 576–772), reflecting the shared β-prism topology of FN3/SPRY folds rather than carbohydrate catalysis. The overall architecture—RING catalytic core, B-box array, COS association module, and FN3/SPRY recognition tail—is diagnostic of TRIM-family E3 ubiquitin ligases and is captured by IPR050617 (E3 ubiquitin-protein ligases and FN3/SPRY domain-containing proteins, residues 3–773).\n\nThis ordered architecture dictates molecular function. The N-terminal RING (IPR001841 with IPR017907) provides the catalytic platform for ubiquitin transfer, while the B-box/C-terminal region (IPR000315, IPR003649) and COS domain (IPR017903) assemble and position the complex on cytosolic structures. The FN3/Ig-like and SPRY/B30.2 modules (IPR003961, IPR013783, IPR043136, IPR001870, IPR003877) create multivalent binding surfaces that determine substrate specificity. Together, this causes robust protein binding (GO:0005515) and E3-ligase-driven assembly, and it mechanistically explains protein autoubiquitination (GO:0051865): the same RING-centered machinery that modifies substrates commonly autoubiquitinates the ligase itself, tuning stability and activity.\n\nFrom molecular function to biological process, the RING-driven ubiquitination machinery directly executes protein autoubiquitination (GO:0051865) and likely extends to broader ubiquitin signaling that modulates cytoskeletal and membrane-proximal pathways. The COS domain and FN3/SPRY tail bias the complex toward cytosolic assemblies, supporting a soluble cytosolic pool (GO:0005829 cytosol) with potential transient association to cytoskeletal and organelle surfaces.\n\nMechanistically, I hypothesize that the RING domain binds an E2 enzyme and catalyzes ubiquitin transfer while the FN3/SPRY tail captures specific targets and adaptors. The COS domain anchors the complex near cytoskeletal tracks or membrane-proximal scaffolds, enhancing encounter rates with substrates. Likely interaction partners include E2 conjugating enzymes (e.g., UBE2D/UBE2E families), cytoskeletal elements and adaptors that localize the ligase to cytosolic structures, and substrate cohorts whose turnover coordinates cytoskeletal dynamics and membrane trafficking. This ensemble of features predicts a cytosolic E3 ligase that self-regulates via autoubiquitination and orchestrates substrate processing through a TRIM-like FN3/SPRY recognition platform.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-Q6ZTA4.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/Q6ZTA4"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/Q6ZTA4/entry","atlas":"/p/Q6ZTA4"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}