{"doi":"10.1074/jbc.m113.495846","title":"Target Specificity of the E3 Ligase LUBAC for Ubiquitin and NEMO Relies on Different Minimal Requirements","abstract":null,"journal":"Journal of Biological Chemistry","year":2013,"id":597200,"datarank":0.6090664515819629,"base_score":4.060443010546419,"endowment":4.060443010546419,"self_citation_contribution":0.6090664515819629,"citation_network_contribution":0.0,"self_endowment_contribution":0.6090664515819629,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":57,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1529920,"name":"Willem J. van Dijk","orcid":null,"position":1,"is_corresponding":false},{"id":556721,"name":"Dris El Atmioui","orcid":null,"position":2,"is_corresponding":false},{"id":737911,"name":"Remco Merkx","orcid":null,"position":3,"is_corresponding":false},{"id":308756,"name":"Huib Ovaa","orcid":"0000-0002-0068-054X","position":4,"is_corresponding":false},{"id":1170050,"name":"Titia K. Sixma","orcid":"0000-0001-6180-0632","position":5,"is_corresponding":false},{"id":1529919,"name":"Judith J. Smit","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Target Specificity of the E3 Ligase LUBAC for Ubiquitin and NEMO Relies on Different Minimal Requirements","abstract":"The ubiquitination of NEMO with linear ubiquitin chains by the E3-ligase LUBAC is important for the activation of the canonical NF-κB pathway. NEMO ubiquitination requires a dual target specificity of LUBAC, priming on a lysine on NEMO and chain elongation on the N terminus of the priming ubiquitin. Here we explore the minimal requirements for these specificities. Effective linear chain formation requires a precise positioning of the ubiquitin N-terminal amine in a negatively charged environment on the top of ubiquitin. Whereas the RBR-LDD region on HOIP is sufficient for targeting the ubiquitin N terminus, the priming lysine modification on NEMO requires catalysis by the RBR domain of HOIL-1L as well as the catalytic machinery of the RBR-LDD domains of HOIP. Consequently, target specificity toward NEMO is determined by multiple LUBAC components, whereas linear ubiquitin chain elongation is realized by a specific interplay between HOIP and ubiquitin.Background: Linear ubiquitination of NEMO by LUBAC is important for NF-κB activation.Results: HOIP and the “top” of ubiquitin are essential for linear ubiquitination, whereas NEMO ubiquitination additionally requires HOIL-1L.Conclusion: NEMO priming and ubiquitin chain elongation rely on different LUBAC contributions.Significance: Novel insights in the requirements for linear ubiquitin chain formation and target selection. The ubiquitination of NEMO with linear ubiquitin chains by the E3-ligase LUBAC is important for the activation of the canonical NF-κB pathway. NEMO ubiquitination requires a dual target specificity of LUBAC, priming on a lysine on NEMO and chain elongation on the N terminus of the priming ubiquitin. Here we explore the minimal requirements for these specificities. Effective linear chain formation requires a precise positioning of the ubiquitin N-terminal amine in a negatively charged environment on the top of ubiquitin. Whereas the RBR-LDD region on HOIP is sufficient for targeting the ubiquitin N terminus, the priming lysine modification on NEMO requires catalysis by the RBR domain of HOIL-1L as well as the catalytic machinery of the RBR-LDD domains of HOIP. Consequently, target specificity toward NEMO is determined by multiple LUBAC components, whereas linear ubiquitin chain elongation is realized by a specific interplay between HOIP and ubiquitin. Background: Linear ubiquitination of NEMO by LUBAC is important for NF-κB activation. Results: HOIP and the “top” of ubiquitin are essential for linear ubiquitination, whereas NEMO ubiquitination additionally requires HOIL-1L. Conclusion: NEMO priming and ubiquitin chain elongation rely on different LUBAC contributions. Significance: Novel insights in the requirements for linear ubiquitin chain formation and target selection.","is_dataset_classified":null,"base_score":4.060443010546419,"endowment":4.060443010546419,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"24030825","pmcid":"PMC3814767","openalex_id":"https://openalex.org/W2002529206","authors":[],"funders":[{"funder_name":"European Research Council","grant_id":"249997","title":null}],"total_grants":1,"fwci":1.6508,"citation_percentile":0.82954877,"influential_citations":0,"citation_trend":[{"year":2014,"count":6},{"year":2015,"count":4},{"year":2016,"count":2},{"year":2017,"count":3},{"year":2018,"count":3},{"year":2019,"count":7},{"year":2020,"count":5},{"year":2021,"count":7},{"year":2022,"count":8},{"year":2023,"count":5},{"year":2024,"count":5},{"year":2025,"count":1},{"year":2026,"count":1}],"oa_status":"hybrid","license":"cc-by","oa_locations":[{"url":"http://www.jbc.org/article/S0021925820486454/pdf","host_type":"journal"},{"url":"http://www.jbc.org/article/S0021925820486454/pdf","host_type":"publisher"},{"url":"https://doi.org/10.1074/jbc.m113.495846","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/24030825","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/3814767","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC3814767","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC3814767?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Ubiquitin and proteasome pathways","Peptidase Inhibition and Analysis","NF-κB Signaling Pathways"],"mesh_terms":["Catalysis","Humans","Multienzyme Complexes","Ubiquitin","Ubiquitin-Protein Ligases","I-kappa B Kinase","Ubiquitination"],"keywords":["Ubiquitin","Ubiquitin ligase","Ubiquitin-Protein Ligases","Lysine","Cell biology","Chemistry","DNA ligase","Priming (agriculture)","Biochemistry","Biology","Amino acid","Enzyme","Gene","Molecular biology","Ubiquitination","E3 ubiquitin ligase","Enzyme Mechanisms","Lubac","Linear Ubiquitin Chain","Rnf31","Nf-κb (Nf-kb)"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"pdb"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-28T12:36:09.564550Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}