{"doi":"10.1091/mbc.e13-11-0697","title":"VWA domain of S5a restricts the ability to bind ubiquitin and Ubl to the 26S proteasome","abstract":"<jats:p>The 26S proteasome recognizes a vast number of ubiquitin-dependent degradation signals linked to various substrates. This recognition is mediated mainly by the stoichiometric proteasomal resident ubiquitin receptors S5a and Rpn13, which harbor ubiquitin-binding domains. Regulatory steps in substrate binding, processing, and subsequent downstream proteolytic events by these receptors are poorly understood. Here we demonstrate that mammalian S5a is present in proteasome-bound and free states. S5a is required for efficient proteasomal degradation of polyubiquitinated substrates and the recruitment of ubiquitin-like (Ubl) harboring proteins; however, S5a-mediated ubiquitin and Ubl binding occurs only on the proteasome itself. We identify the VWA domain of S5a as a domain that limits ubiquitin and Ubl binding to occur only upon proteasomal association. Multiubiquitination events within the VWA domain can further regulate S5a association. Our results provide a molecular explanation to how ubiquitin and Ubl binding to S5a is restricted to the 26S proteasome.</jats:p>","journal":"Molecular Biology of the Cell","year":2014,"id":597249,"datarank":0.4335557636844247,"base_score":2.8903717578961645,"endowment":2.8903717578961645,"self_citation_contribution":0.4335557636844247,"citation_network_contribution":0.0,"self_endowment_contribution":0.4335557636844247,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":17,"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":1530060,"name":"Ilana Braunstein","orcid":null,"position":1,"is_corresponding":false},{"id":1530061,"name":"Elada Isakov","orcid":null,"position":2,"is_corresponding":false},{"id":1530062,"name":"Tamar Ziv","orcid":null,"position":3,"is_corresponding":false},{"id":934099,"name":"Ami Navon","orcid":"0000-0001-6316-7818","position":4,"is_corresponding":false},{"id":1185707,"name":"Shenhav Cohen","orcid":null,"position":5,"is_corresponding":false},{"id":17926,"name":"Ariel Stanhill","orcid":"0000-0002-0318-2212","position":6,"is_corresponding":false},{"id":1530059,"name":"Ravit Piterman","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"VWA domain of S5a restricts the ability to bind ubiquitin and Ubl to the 26S proteasome","abstract":"<jats:p>The 26S proteasome recognizes a vast number of ubiquitin-dependent degradation signals linked to various substrates. This recognition is mediated mainly by the stoichiometric proteasomal resident ubiquitin receptors S5a and Rpn13, which harbor ubiquitin-binding domains. Regulatory steps in substrate binding, processing, and subsequent downstream proteolytic events by these receptors are poorly understood. Here we demonstrate that mammalian S5a is present in proteasome-bound and free states. S5a is required for efficient proteasomal degradation of polyubiquitinated substrates and the recruitment of ubiquitin-like (Ubl) harboring proteins; however, S5a-mediated ubiquitin and Ubl binding occurs only on the proteasome itself. We identify the VWA domain of S5a as a domain that limits ubiquitin and Ubl binding to occur only upon proteasomal association. Multiubiquitination events within the VWA domain can further regulate S5a association. Our results provide a molecular explanation to how ubiquitin and Ubl binding to S5a is restricted to the 26S proteasome.</jats:p>","is_dataset_classified":null,"base_score":2.8903717578961645,"endowment":2.8903717578961645,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"25318673","pmcid":"PMC4263443","openalex_id":"https://openalex.org/W2141223333","authors":[],"funders":[],"total_grants":0,"fwci":0.7798,"citation_percentile":0.71037918,"influential_citations":0,"citation_trend":[{"year":2015,"count":3},{"year":2016,"count":3},{"year":2018,"count":1},{"year":2019,"count":3},{"year":2021,"count":1},{"year":2022,"count":1},{"year":2023,"count":3},{"year":2024,"count":1},{"year":2026,"count":1}],"oa_status":"green","license":null,"oa_locations":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/4263443","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/4263443","host_type":"repository"},{"url":"https://doi.org/10.1091/mbc.e13-11-0697","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/25318673","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC4263443","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC4263443?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Ubiquitin and proteasome pathways","Endoplasmic Reticulum Stress and Disease","Autophagy in Disease and Therapy","Activating Transcription Factor 4","Amino Acid Sequence","Animals","HEK293 Cells","Humans","Male","Mice","Molecular Sequence Data","Polyubiquitin","Proteasome Endopeptidase Complex","Protein Binding","Protein Interaction Domains and Motifs","Proteolysis","RNA-Binding Proteins","Ubiquitin","Ubiquitinated Proteins","Ubiquitination"],"mesh_terms":["Amino Acid Sequence","Animals","Humans","Male","Molecular Sequence Data","Protein Binding","RNA-Binding Proteins","Ubiquitin","Polyubiquitin","Proteasome Endopeptidase Complex","Mice","Activating Transcription Factor 4","Protein Interaction Domains and Motifs","Ubiquitination","Ubiquitinated Proteins","HEK293 Cells","Proteolysis"],"keywords":["Ubiquitin","Proteasome","Biology","Ubiquitins","Ubiquitin ligase","Plasma protein binding","Ubiquitin-conjugating enzyme","Proteolysis","Cell biology","Ubiquitin-Protein Ligases","DNA-binding protein","Biochemistry","Enzyme","Transcription factor","Gene"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-28T12:44:09.900792Z","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":[]}