{"doi":"10.17615/4twx-3c24","title":"The N-terminal Domain Allosterically Regulates Cleavage and Activation of the Epithelial Sodium Channel","abstract":"The epithelial sodium channel (ENaC) is activated upon endoproteolytic cleavage of specific segments in the extracellular domains of the α- and γ-subunits. Cleavage is accomplished by intracellular proteases prior to membrane insertion and by surface-expressed or extracellular soluble proteases once ENaC resides at the cell surface. These cleavage events are partially regulated by intracellular signaling through an unknown allosteric mechanism. Here, using a combination of computational and experimental techniques, we show that the intracellular N terminus of γ-ENaC undergoes secondary structural transitions upon interaction with phosphoinositides. From ab initio folding simulations of the N termini in the presence and absence of phosphatidylinositol 4,5-bisphosphate (PIP2), we found that PIP2 increases α-helical propensity in the N terminus of γ-ENaC. Electrophysiology and mutation experiments revealed that a highly conserved cluster of lysines in the γ-ENaC N terminus regulates accessibility of extracellular cleavage sites in γ-ENaC. We also show that conditions that decrease PIP2 or enhance ubiquitination sharply limit access of the γ-ENaC extracellular domain to proteases. Further, the efficiency of allosteric control of ENaC proteolysis is dependent on Tyr370 in γ-ENaC. Our findings provide an allosteric mechanism for ENaC activation regulated by the N termini and sheds light on a potential general mechanism of channel and receptor activation.","journal":"UNC Libraries","year":2020,"id":135908,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9472,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":522486,"name":"Yan L. Dang","orcid":"0000-0002-8986-7406","position":1,"is_corresponding":false},{"id":531528,"name":"M. Jackson Stutts","orcid":"0000-0002-3159-7802","position":2,"is_corresponding":false},{"id":368639,"name":"Hong He","orcid":"0000-0001-7778-1202","position":3,"is_corresponding":false},{"id":284291,"name":"Guilherme J. M. Garcia","orcid":"0000-0003-2995-9226","position":4,"is_corresponding":false},{"id":325621,"name":"Pradeep Kota","orcid":"0000-0002-2825-5123","position":5,"is_corresponding":false},{"id":149320,"name":"Nikolay V. Dokholyan","orcid":"0000-0002-8225-4025","position":6,"is_corresponding":false},{"id":594184,"name":"Ginka Buchner","orcid":null,"position":7,"is_corresponding":false},{"id":593435,"name":"Hirak Chakraborty","orcid":"0000-0001-7499-5707","position":8,"is_corresponding":false},{"id":593436,"name":"Jan Kubelka","orcid":"0000-0003-4943-7732","position":9,"is_corresponding":false},{"id":402971,"name":"Martina Gentzsch","orcid":"0000-0002-9435-0321","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:16:35.237665Z","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":[]}