{"uniprot":"O60810","gene":"PRAMEF4","name":"PRAME family member 4","organism":"Homo sapiens (Human)","status":"dark","length":478,"sequence":"MKMSIWTPPRLLELAGRSLLRDQALAMSTLEELPTELFPPLFMEAFSRRRCEALKLMVQSWPFRRLPLRPLIKMPCLEAFQAVLDGLDALLNLGVRPRRWKLQVLDLQDVCENFWMVWSEAMAHGCFLNAKRNKKPVEDCPRMKGRQPLTVFVELWLKNRTLDEYLTCLLLWVKQRKDLLHLCCKKLKILGMPFRNIRSILKMVNLDCIQEVEVNCKWVLPILTQFTPYLGHMRNLQKLILSHMDVSRYVSPEQKKEIVTQFTTQFLKLRCLQKLYMNSVSFLEGHLDQLLSCLKTSLKFLTITNCVLLESDLKHLSQCPSISQLKTLDLSGIRLTNYSLVPLQILLEKVAATLEYLDLDDCGIIDSQVNAILPALSRCFELNTFSFCGNPICMATLENLLSHTIILKNLCVELYPAPRESYGADGTLCWSRFAQIRAELMNRVRDLRHPKRILFCTDYCPDCGNRSFYDLEADQYCC","function_summary":"A soluble adaptor that uses an N-terminal PRAME-like module and a C-terminal leucine-rich repeat scaffold to recruit specific substrates to a Cul2-RING ubiquitin ligase. By assembling and positioning targets for efficient polyubiquitylation, it promotes their proteasome-dependent turnover and thereby contributes to pathways that govern cell-cycle control and cellular differentiation. Its nucleocytoplasmic scaffold architecture enables high-specificity substrate capture and handoff within cullin-based ubiquitination assemblies.","plain_language":"PRAMEF4 has barely been studied. The model's best guess: A soluble adaptor that uses an N-terminal PRAME-like module and a C-terminal leucine-rich repeat scaffold to recruit specific substrates to a Cul2-RING ubiquitin ligase. By assembling and positioning targets for efficient polyubiquitylation, it promotes their proteasome-dependent turnover and thereby contributes to pathways that govern cell-cycle control and cellular differentiation.","uniprot_summary":"May be involved in cell-cycle regulation and cellular differentiation.","go_terms":{"molecular_function":[{"id":"GO:1990756","label":"ubiquitin ligase-substrate adaptor activity"}],"biological_process":[{"id":"GO:0043161","label":"proteasome-mediated ubiquitin-dependent protein catabolic process"}],"cellular_component":[{"id":"GO:0031462","label":"Cul2-RING ubiquitin ligase complex"}]},"interpro":[{"id":"IPR032675","name":"Leucine-rich repeat domain superfamily","type":"homologous_superfamily","start":155,"end":413},{"id":"IPR060378","name":"PRAME-like, N-terminal domain","type":"domain","start":8,"end":115},{"id":"IPR060377","name":"PRAME-like, C-terminal LRR domain","type":"domain","start":149,"end":478},{"id":"IPR026271","name":"PRAME","type":"family","start":3,"end":476},{"id":"IPR050694","name":"LRRC14/PRAME","type":"family","start":3,"end":464}],"reasoning":"I begin with the InterPro architecture. The N-terminus carries IPR060378 (PRAME-like, N-terminal domain, residues 8–115), followed by an extended leucine-rich repeat scaffold defined by IPR032675 (Leucine-rich repeat domain superfamily, residues 155–413) and IPR060377 (PRAME-like, C-terminal LRR domain, residues 149–478). Two family-level envelopes, IPR026271 (PRAME family, residues 3–476) and IPR050694 (LRRC14/PRAME family, residues 3–464), span essentially the full length, indicating a conserved PRAME/LRRC14 adaptor framework. The ordered layout—an N-terminal PRAME-like module feeding into a long LRR array—creates a bipartite recognition platform: the N-terminal PRAME-like domain often mediates initial docking to partner proteins, while the LRR solenoid provides a curved surface for high-specificity substrate capture and assembly of larger complexes.\n\nThis architecture causes adaptor activity rather than catalysis. LRR arrays are classical specificity modules in ubiquitin ligase pathways, and the PRAME/LRRC14 family is known for assembling substrate-adaptor functions. Such a scaffold naturally confers GO:1990756 ubiquitin ligase-substrate adaptor activity: the N-terminal PRAME-like domain nucleates association with cullin-RING machinery, and the C-terminal LRR domain presents a multivalent interface that selects targets for ubiquitination.\n\nFrom this molecular function, the biological role follows. By recruiting substrates to cullin-RING assemblies, the protein drives GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process. The LRR-guided capture of targets and their handoff to E3 complexes channels them into polyubiquitylation and subsequent proteasomal turnover, a pathway central to cell-cycle control and differentiation.\n\nThe cellular context is dictated by the complex it assembles with. The presence of a PRAME/LRRC14 scaffold and the inferred role as a substrate adaptor point to operation within a cullin-based E3 environment, specifically the GO:0031462 Cul2-RING ubiquitin ligase complex. Such complexes function in both cytoplasm and nucleus; the absence of transmembrane features and the soluble LRR scaffold support a nucleocytoplasmic adaptor that shuttles between assembly sites of CRL2.\n\nMechanistically, I hypothesize that the N-terminal PRAME-like domain engages core CRL2 components, while the LRR array recognizes specific substrate cohorts whose abundance must be tightly tuned during differentiation and cell-cycle transitions. Likely partners include the Cul2 scaffold and RING catalytic subunits, with auxiliary adaptors stabilizing the assembly. This arrangement positions the protein as a selective bridge that captures substrates and delivers them to the Cul2-RING catalytic center for efficient polyubiquitylation and proteasomal routing.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-O60810.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/O60810"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/O60810/entry","atlas":"/p/O60810"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}