{"uniprot":"A8MQ27","gene":"NEURL1B","name":"E3 ubiquitin-protein ligase NEURL1B","organism":"Homo sapiens (Human)","status":"dark","length":555,"sequence":"MGNTVHRTLPDPSPPARLLATRPCCGPGPERRPVLGEAPRFHAQAKGKNVRLDGHSRRATRRNSFCNGVTFTQRPIRLYEQVRLRLVAVRPGWSGALRFGFTAHDPSLMSAQDIPKYACPDLVTRPGYWAKALPENLALRDTVLAYWADRHGRVFYSVNDGEPVLFHCGVAVGGPLWALIDVYGITDEVQLLESAFADTLTPARLSQARFSACLPPSSHDAANFDNNELENNQVVAKLGHLALGRAPGPPPADAAAAAIPCGPRERPRPASSPALLEADLRFHATRGPDVSLSADRKVACAPRPDGGRTLVFSERPLRPGESLFVEVGRPGLAAPGALAFGITSCDPGVLRPNELPADPDALLDRKEYWVVARAGPVPSGGDALSFTLRPGGDVLLGINGRPRGRLLCVDTTQALWAFFAVRGGVAGQLRLLGTLQSSPATTTPSGSLSGSQDDSDSDMTFSVNQSSSASESSLVTAPSSPLSPPVSPVFSPPEPAGIKNGECTVCFDGEVDTVIYTCGHMCLCHSCGLRLKRQARACCPICRRPIKDVIKIYRP","function_summary":"A cytosolic adaptor and ubiquitin-system scaffold that organizes endocytic and trafficking assemblies. Its N-terminal recognition platform binds cargo and endocytic adaptors, while a C-terminal RING module provides ubiquitin-coupled signaling that promotes vesicle formation and cargo sorting. By coupling membrane trafficking to actin-associated assemblies, it coordinates endocytosis and broader intracellular transport pathways within cytosolic and actin-enriched regions.","plain_language":"NEURL1B has barely been studied. The model's best guess: A cytosolic adaptor and ubiquitin-system scaffold that organizes endocytic and trafficking assemblies. Its N-terminal recognition platform binds cargo and endocytic adaptors, while a C-terminal RING module provides ubiquitin-coupled signaling that promotes vesicle formation and cargo sorting.","uniprot_summary":"May be involved in endocytosis and cytoskeletal organization.","go_terms":{"molecular_function":[{"id":"GO:0005515","label":"protein binding"}],"biological_process":[{"id":"GO:0015031","label":"protein transport"},{"id":"GO:0006897","label":"endocytosis"}],"cellular_component":[{"id":"GO:0005829","label":"cytosol"},{"id":"GO:0015629","label":"actin cytoskeleton"}]},"interpro":[{"id":"IPR043136","name":"B30.2/SPRY domain superfamily","type":"homologous_superfamily","start":40,"end":193},{"id":"IPR043136","name":"B30.2/SPRY domain superfamily","type":"homologous_superfamily","start":281,"end":430},{"id":"IPR013083","name":"Zinc finger, RING/FYVE/PHD-type","type":"homologous_superfamily","start":497,"end":555},{"id":"IPR006573","name":"Neuralized homology repeat (NHR) domain","type":"domain","start":36,"end":194},{"id":"IPR006573","name":"Neuralized homology repeat (NHR) domain","type":"domain","start":277,"end":433},{"id":"IPR001841","name":"Zinc finger, RING-type","type":"domain","start":503,"end":543},{"id":"IPR037962","name":"Neuralized","type":"family","start":35,"end":554}],"reasoning":"I begin with the domain architecture. The N-terminus contains IPR043136 (B30.2/SPRY domain superfamily, residues 40–193) and a second SPRY superfamily block IPR043136 (residues 281–430). These two β-sandwich modules are embedded within tandem Neuralized homology repeat regions: IPR006573 (NHR domain, residues 36–194) at the N-terminus and IPR006573 (NHR domain, residues 277–433) centrally. This tandem SPRY–NHR layout is characteristic of Neuralized-family adaptors that recognize short linear motifs and assemble endocytic and cytoskeletal complexes. The C-terminus carries a catalytic scaffold: IPR013083 (Zinc finger, RING/FYVE/PHD-type superfamily, residues 497–555) with a defined IPR001841 RING-type zinc finger (residues 503–543). The overall architecture is consolidated by IPR037962 (Neuralized family, residues 35–554), which ties the N-terminal recognition platform to a C-terminal RING module.\n\nThis architecture dictates molecular function. The paired SPRY and NHR domains create a high-affinity, multivalent binding surface that captures cargo and accessory factors; this directly supports GO:0005515 protein binding as a core activity. The C-terminal RING finger provides a catalytic hub that coordinates zinc and organizes E2-conjugating enzymes, enabling ubiquitin transfer. In Neuralized-family proteins, this RING module frequently drives endocytic sorting and membrane remodeling. Thus, the N-terminal recognition platform causes selective assembly of cargo/adaptor complexes, while the RING domain supplies ubiquitin-dependent signaling or membrane-curvature coupling.\n\nFrom these molecular activities, the biological processes follow. Ubiquitin-coupled assembly of endocytic machinery and cargo-sorting complexes positions the protein squarely in GO:0006897 endocytosis. The same modular binding and ubiquitin signaling propagate through vesicular pathways and cytoskeletal tracks, aligning with GO:0015031 protein transport. The SPRY–NHR scaffold is well-suited to coordinate actin-associated adaptors and membrane-associated cargo, explaining how transport and endocytosis are mechanistically linked.\n\nCellular location is inferred from the soluble, modular nature of the domains and their cytoskeletal couplings. The absence of transmembrane segments and the presence of extensive interaction modules indicate a soluble cytoplasmic pool, consistent with GO:0005829 cytosol. The coupling of endocytic assemblies to filament networks via NHR/SPRY-mediated adaptor binding rationalizes association with GO:0015629 actin cytoskeleton. Together, these features place the protein in cytosolic and actin-enriched endocytic zones.\n\nMechanistically, I hypothesize that the N-terminal SPRY/NHR tandem recruits endocytic adaptors and cargo bearing internalization motifs, while the C-terminal RING finger catalyzes ubiquitin signaling that licenses vesicle budding and cargo sorting. This dual-module system likely nucleates transient complexes that bridge membrane trafficking with actin remodeling. Likely partners include clathrin-associated adaptors and actin regulators that operate at endocytic hotspots and along cytoskeletal tracks.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-A8MQ27.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/A8MQ27"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/A8MQ27/entry","atlas":"/p/A8MQ27"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}