{"doi":"10.1016/j.jbc.2024.105715","title":"NEDD4L intramolecular interactions regulate its auto and substrate NaV1.5 ubiquitination","abstract":"NEDD4L is a HECT-type E3 ligase that catalyzes the addition of ubiquitin to intracellular substrates such as the cardiac voltage-gated sodium channel, Na V 1.5. The intramolecular interactions of NEDD4L regulate its enzymatic activity which is essential for proteostasis. For Na V 1.5, this process is critical as alterations in Na + current is involved in cardiac diseases including arrhythmias and heart failure. In this study, we perform extensive biochemical and functional analyses that implicate the C2 domain and the first WW-linker (1,2-linker) in the auto-regulatory mechanism of NEDD4L. Through in vitro and electrophysiological experiments, the NEDD4L 1,2-linker was determined to be important in substrate ubiquitination of Na V 1.5. We establish the preferred sites of ubiquitination of NEDD4L to be in the second WW-linker (2,3-linker). Interestingly, NEDD4L ubiquitinates the cytoplasmic linker between the first and second transmembrane domains of the channel (DI-DII) of Na V 1.5. Moreover, we design a genetically encoded modulator of Nav1.5 that achieves Na + current reduction using the NEDD4L HECT domain as cargo of a Na V 1.5-binding nanobody. These investigations elucidate the mechanisms regulating the NEDD4 family and furnish a new molecular framework for understanding Na V 1.5 ubiquitination.","journal":"Journal of Biological Chemistry","year":2024,"id":436126,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9534,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":286187,"name":"Sara Nathan","orcid":"0000-0002-0090-0303","position":1,"is_corresponding":false},{"id":6635,"name":"Hanjie Jiang","orcid":"0000-0001-6090-4552","position":2,"is_corresponding":false},{"id":1141776,"name":"Wendy Xia","orcid":null,"position":3,"is_corresponding":false},{"id":1141402,"name":"H Kim","orcid":"0009-0001-2658-3510","position":4,"is_corresponding":false},{"id":484269,"name":"Nourdine Chakouri","orcid":"0000-0002-8809-8684","position":5,"is_corresponding":false},{"id":934876,"name":"Justin N. Nwafor","orcid":"0000-0001-5348-6196","position":6,"is_corresponding":false},{"id":1244229,"name":"Lucile Fossier","orcid":"0000-0002-1837-9093","position":7,"is_corresponding":false},{"id":495687,"name":"S. Lakshmi","orcid":"0000-0002-0014-4018","position":8,"is_corresponding":false},{"id":907287,"name":"Zan Chen","orcid":"0000-0001-9925-872X","position":9,"is_corresponding":false},{"id":299275,"name":"Tatiana Boronina","orcid":"0000-0001-5270-3849","position":10,"is_corresponding":false},{"id":1244230,"name":"Jeremy Post","orcid":"0000-0003-2490-1586","position":11,"is_corresponding":false},{"id":475840,"name":"Suman Paul","orcid":"0000-0001-9357-3702","position":12,"is_corresponding":false},{"id":299276,"name":"Robert N. Cole","orcid":"0000-0002-3096-4754","position":13,"is_corresponding":false},{"id":484278,"name":"Manu Ben‐Johny","orcid":"0000-0002-5645-0815","position":14,"is_corresponding":false},{"id":67,"name":"Philip A. Cole","orcid":"0000-0001-6873-7824","position":15,"is_corresponding":false},{"id":434249,"name":"Sandra B. Gabelli","orcid":"0000-0003-1205-5204","position":16,"is_corresponding":false},{"id":618196,"name":"Katharine M. Wright","orcid":"0000-0001-9060-3849","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-19T02:00:12.706156Z","pmid":"38309503","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":[]}