{"uniprot":"A6NGH8","gene":"ANKRD61","name":"Ankyrin repeat domain-containing protein 61","organism":"Homo sapiens (Human)","status":"dark","length":418,"sequence":"MGNITRKGSRDLVVDSAKSLEDGPSAALHSKLYEAIMREDCTTIEVLLRNHPVNQPITILPNSASNRLLLTQPTESIIPIHLAAKYHKAQSLLCLLRHGADPEVRDTTGLTTLNLMLLHWPVTSTTWAKPGNRTHRILTDIQNSSITCLRILCAHGAQVNTQGEISNKRSPLHLAIAYGCYPVLSILTQNGADVNAINEASMTPLHMAANMLNKEMMETLIAYGANVNCAVSSTGNTPLKLAVCTASSKAGRLLGAGVSCIRLLLTHGAKVNAQDYKGQTAIHEACFGGREAIINLLLEFEANVNILTRNGESPIYMYLQRSCNVRDTALLARLLYHTYPLRMTNNQGILPAGIMLPEFRLLRDTLIKQSQKPLSLQGICKRNIRNIYGEKYKQHLKQFLPVTIWNSVYCCYDLAYTS","function_summary":"A soluble nuclear adaptor that uses a tandem ankyrin-repeat scaffold to capture protein substrates and a SOCS-box-like module to recruit Elongin–Cullin ubiquitin ligase cores. By assembling these complexes in the nucleoplasm, it enhances substrate ubiquitination and directs their modification-dependent turnover, thereby tuning nuclear pathways and cellular responses to organic cyclic compounds through selective proteostasis.","plain_language":"ANKRD61 has barely been studied. The model's best guess: A soluble nuclear adaptor that uses a tandem ankyrin-repeat scaffold to capture protein substrates and a SOCS-box-like module to recruit Elongin–Cullin ubiquitin ligase cores. By assembling these complexes in the nucleoplasm, it enhances substrate ubiquitination and directs their modification-dependent turnover, thereby tuning nuclear pathways and cellular responses to organic cyclic compounds through selective proteostasis.","uniprot_summary":"May be a substrate recognition component of a SCF-like ECS (Elongin-Cullin-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.","go_terms":{"molecular_function":[{"id":"GO:0005515","label":"protein binding"}],"biological_process":[{"id":"GO:0071310","label":"cellular response to organic cyclic compound"},{"id":"GO:0045862","label":"positive regulation of proteolysis"},{"id":"GO:0030163","label":"protein catabolic process"},{"id":"GO:0006511","label":"ubiquitin-dependent protein catabolic process"},{"id":"GO:0019941","label":"modification-dependent protein catabolic process"},{"id":"GO:0031398","label":"positive regulation of protein ubiquitination"}],"cellular_component":[{"id":"GO:0005654","label":"nucleoplasm"}]},"interpro":[{"id":"IPR036770","name":"Ankyrin repeat-containing domain superfamily","type":"homologous_superfamily","start":12,"end":337},{"id":"IPR050663","name":"Ankyrin Repeat and SOCS Box","type":"family","start":145,"end":320},{"id":"IPR002110","name":"Ankyrin repeat","type":"repeat","start":75,"end":107},{"id":"IPR002110","name":"Ankyrin repeat","type":"repeat","start":167,"end":232},{"id":"IPR002110","name":"Ankyrin repeat","type":"repeat","start":234,"end":317}],"reasoning":"I begin with the InterPro architecture. The polypeptide is dominated by IPR036770 (Ankyrin repeat-containing domain superfamily, residues 12–337), indicating a solenoid scaffold built from tandem ankyrin repeats that specialize in high-specificity protein recognition. This scaffold is reinforced by three discrete ankyrin repeat signatures: IPR002110 (Ankyrin repeat, residues 75–107), IPR002110 (Ankyrin repeat, residues 167–232), and IPR002110 (Ankyrin repeat, residues 234–317). The ordered array of ankyrin repeats creates an extended binding groove that captures folded substrates and adaptor proteins. Embedded within this ankyrin framework is IPR050663 (Ankyrin Repeat and SOCS Box family, residues 145–320). Membership in the ankyrin/SOCS-box family signals a C-terminal SOCS-box-like module that recruits Elongin B/C and couples to Cullin–RING ligase cores. Even though the SOCS box is inferred rather than individually mapped here, the family assignment functionally links the ankyrin scaffold to ubiquitin pathway machinery.\n\nThis architecture dictates the molecular function. The ankyrin repeat array confers avid, selective protein binding, aligning with GO:0005515 protein binding. The ankyrin scaffold does not catalyze ubiquitin transfer itself; instead, it binds both substrates and E3-ligase assemblies. The SOCS-box-like module provides the docking surface for Elongin BC and Cullin adaptors, positioning the ankyrin-bound substrate for ubiquitin conjugation.\n\nFrom this binding-driven mechanism, the biological processes follow. By recruiting Elongin BC–Cullin complexes through its SOCS-box-like region, the protein promotes substrate polyubiquitination, which corresponds to GO:0031398 positive regulation of protein ubiquitination. Ubiquitination commits targets to GO:0006511 ubiquitin-dependent protein catabolic process and GO:0019941 modification-dependent protein catabolic process, typically via the proteasome or lysosomal routes. The ankyrin platform’s ability to recognize diverse substrates explains how it can both enhance ubiquitination and drive their degradation. The inclusion of GO:0071310 cellular response to organic cyclic compound is consistent with this regulatory axis: many ubiquitin pathway substrates and modulators are transcriptional or metabolic effectors responsive to cyclic metabolites or hormones, and an ankyrin/SOCS-box adaptor can tune these pathways by selective turnover.\n\nCellular location is inferred from function and architecture. The absence of transmembrane segments and the soluble ankyrin scaffold favor a non-membranous compartment. The provided nucleoplasmic context is mechanistically coherent: nuclear substrates of transcription, chromatin, and RNA processing frequently undergo ubiquitin-mediated control. Thus, the most precise compartment is GO:0005654 nucleoplasm, where substrate capture and E3-ligase assembly can be coordinated.\n\nThese features suggest a mechanistic model. The ankyrin repeats (IPR036770; IPR002110 repeats at residues 75–107, 167–232, and 234–317) form a substrate-recognition platform that binds nuclear proteins. The SOCS-box-like region (IPR050663) recruits Elongin B/C and couples to Cullin–RING cores, thereby stimulating substrate ubiquitination and subsequent degradation. In the nucleoplasm, this adaptor likely tunes transcriptional and RNA-processing circuits and can mediate responses to organic cyclic compounds by adjusting the stability of pathway regulators.\n\nFrom this mechanism, I hypothesize interactions with Elongin B and C and assembly onto Cullin–RING ligases (e.g., CUL2- or CUL5-based cores), as well as transient contacts with E2 conjugating enzymes and the proteasome. Substrate partners are expected to be nuclear proteins whose levels are dynamically controlled by ubiquitination, including transcriptional repressors/activators and RNA-processing factors that change in response to metabolic cues.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-A6NGH8.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/A6NGH8"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/A6NGH8/entry","atlas":"/p/A6NGH8"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}