{"uniprot":"Q3SXM0","gene":"DCAF4L1","name":"DDB1- and CUL4-associated factor 4-like protein 1","organism":"Homo sapiens (Human)","status":"dark","length":396,"sequence":"MEAERLRLLEEEAKLKKVARMGFNASSMLRKSQLGFLNVTSYSRLANELRVSCMERKKVQIRSLDPSSLASDRFNFILASTNSDQLFVVNQVEVEGSKYGIISLRTLKIPSFHVYVLRNLYVPNRKVKSLCWASLNQLDSHVLLCFEGITDAPSCAVLLPASRFLSVHTRVNQPGMLCSFQIPEAWSCAWSLNTRAYHCFSAGLSQQVLLTSVATGHQQSFDTSSDVLAQQFASTAPLLFNGCRSGEIFAIDLRCRNRGKGWRATRLFHDSAVTSVQILQEEQCLMASDMTGKIKLWDLRATKCVRQYEGHVNESAYLPLHVHEEEGIVVAVGQDCYTRIWSLHDAHLLRTIPSPYSASEDDIPSVAFASRLGGIRGAAPGLLMAVRQDLYCFPFS","function_summary":"A nucleoplasmic adaptor that uses a WD40 β-propeller scaffold to bind and present nuclear protein substrates to a cullin-RING ubiquitin ligase. By acting as a substrate receptor for a CUL4–DDB1 complex, it recruits specific nucleoplasmic clients for polyubiquitination and subsequent proteasomal degradation, thereby tuning nuclear protein turnover and indirectly shaping transcriptional and genome-maintenance pathways.","plain_language":"DCAF4L1 has barely been studied. The model's best guess: A nucleoplasmic adaptor that uses a WD40 β-propeller scaffold to bind and present nuclear protein substrates to a cullin-RING ubiquitin ligase. By acting as a substrate receptor for a CUL4–DDB1 complex, it recruits specific nucleoplasmic clients for polyubiquitination and subsequent proteasomal degradation, thereby tuning nuclear protein turnover and indirectly shaping transcriptional and genome-maintenance pathways.","uniprot_summary":"Probable substrate receptor for the CUL4-DDB1 E3 ubiquitin-protein ligase complex.","go_terms":{"molecular_function":[{"id":"GO:0005515","label":"protein binding"}],"biological_process":[{"id":"GO:0043161","label":"proteasome-mediated ubiquitin-dependent protein catabolic process"}],"cellular_component":[{"id":"GO:0005654","label":"nucleoplasm"}]},"interpro":[{"id":"IPR015943","name":"WD40/YVTN repeat-like-containing domain superfamily","type":"homologous_superfamily","start":67,"end":375},{"id":"IPR036322","name":"WD40-repeat-containing domain superfamily","type":"homologous_superfamily","start":122,"end":367},{"id":"IPR052254","name":"CUL4-DDB1 E3 ligase complex substrate receptor","type":"family","start":1,"end":395},{"id":"IPR001680","name":"WD40 repeat","type":"repeat","start":260,"end":342}],"reasoning":"I begin with the InterPro architecture. The sequence is dominated by WD40-like modules: IPR015943 (WD40/YVTN repeat-like-containing domain superfamily, residues 67–375) and IPR036322 (WD40-repeat-containing domain superfamily, residues 122–367) together define a β-propeller scaffold that typically mediates selective protein recognition rather than catalysis. Within this scaffold sits IPR001680 (WD40 repeat, residues 260–342), reinforcing the presence of a canonical seven-bladed β-propeller core that presents a rigid, solvent-exposed surface for multivalent binding. Critically, the entire polypeptide is classified as IPR052254 (CUL4-DDB1 E3 ligase complex substrate receptor family, residues 1–395), which specifies that this WD40 propeller functions as a substrate receptor for the CUL4-DDB1 cullin-RING ubiquitin ligase. The ordered layout—an N-to-C span of a single WD40-centered propeller that fully occupies the substrate-receptor family envelope—causes high-affinity, sequence-agnostic protein binding suited to recruit targets to ubiquitination machinery.\n\nThis WD40 β-propeller architecture dictates the molecular function as protein binding (GO:0005515). WD40 repeats lack intrinsic catalytic residues but excel at forming stable, planar binding platforms that read short linear motifs or post-translational marks on client proteins. The IPR052254 family assignment causally links this binding to substrate selection for a cullin-RING ligase, positioning the protein as the adaptor that confers specificity to ubiquitin transfer.\n\nFrom this binding-driven adaptor role, the biological process follows: substrate delivery to a CUL4-DDB1 E3 ligase triggers polyubiquitination and subsequent degradation by the 26S proteasome. This places the protein squarely in proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161). By recruiting specific nuclear substrates to the ligase, the protein drives timely turnover that tunes gene expression and genome maintenance pathways.\n\nCellular localization is inferred from function and architecture. Substrate receptors of CUL4-DDB1 commonly operate where chromatin-associated targets reside. The absence of transmembrane segments and the role in nuclear protein quality control support a soluble nuclear localization, specifically the nucleoplasm (GO:0005654). A nucleoplasmic setting allows efficient surveillance of transcriptional regulators and DNA repair factors that require regulated ubiquitination.\n\nMechanistically, the WD40 propeller likely forms a substrate-recognition cradle that docks both the DDB1 adaptor and target proteins. This geometry positions lysine-bearing regions of clients for ubiquitin transfer from the associated E2 via the CUL4 catalytic core. I hypothesize that it transiently assembles with DDB1 and CUL4A/B to form a CRL4 complex, and it may preferentially capture nucleoplasmic clients such as chromatin-associated factors or transcriptional repressors. Likely interaction partners therefore include the CRL4 core (DDB1, CUL4A/B), nuclear E2 conjugating enzymes, and nucleoplasmic substrates whose turnover coordinates transcription and DNA-associated processes.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-Q3SXM0.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/Q3SXM0"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/Q3SXM0/entry","atlas":"/p/Q3SXM0"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}