{"doi":"10.7554/elife.86151","title":"The neuronal calcium sensor NCS-1 regulates the phosphorylation state and activity of the Gα chaperone and GEF Ric-8A","abstract":"The neuronal calcium sensor 1 (NCS-1), an EF-hand Ca 2+ binding protein, and Ric-8A coregulate synapse number and probability of neurotransmitter release. Recently, the structures of Ric-8A bound to Gα have revealed how Ric-8A phosphorylation promotes Gα recognition and activity as a chaperone and guanine nucleotide exchange factor. However, the molecular mechanism by which NCS-1 regulates Ric-8A activity and its interaction with Gα subunits is not well understood. Given the interest in the NCS-1/Ric-8A complex as a therapeutic target in nervous system disorders, it is necessary to shed light on this molecular mechanism of action at atomic level. We have reconstituted NCS-1/Ric-8A complexes to conduct a multimodal approach and determine the sequence of Ca 2+ signals and phosphorylation events that promote the interaction of Ric-8A with Gα. Our data show that the binding of NCS-1 and Gα to Ric-8A are mutually exclusive. Importantly, NCS-1 induces a structural rearrangement in Ric-8A that traps the protein in a conformational state that is inaccessible to casein kinase II-mediated phosphorylation, demonstrating one aspect of its negative regulation of Ric-8A-mediated G-protein signaling. Functional experiments indicate a loss of Ric-8A guanine nucleotide exchange factor (GEF) activity toward Gα when complexed with NCS-1, and restoration of nucleotide exchange activity upon increasing Ca 2+ concentration. Finally, the high-resolution crystallographic data reported here define the NCS-1/Ric-8A interface and will allow the development of therapeutic synapse function regulators with improved activity and selectivity.","journal":"eLife","year":2023,"id":371877,"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":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9438,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":499200,"name":"Levi J. McClelland","orcid":"0000-0002-0868-8925","position":1,"is_corresponding":false},{"id":1011749,"name":"Sandra Arroyo‐Urea","orcid":"0000-0003-3785-298X","position":2,"is_corresponding":false},{"id":1012264,"name":"Sonia Sánchez-Yepes","orcid":null,"position":3,"is_corresponding":false},{"id":1011750,"name":"Juan Sabín","orcid":"0000-0001-6550-5702","position":4,"is_corresponding":false},{"id":1012265,"name":"Sara Pérez-Suárez","orcid":null,"position":5,"is_corresponding":false},{"id":1011751,"name":"Margarita Menéndez","orcid":"0000-0002-3267-4443","position":6,"is_corresponding":false},{"id":1011752,"name":"Alicia Mansilla","orcid":"0000-0002-2192-5112","position":7,"is_corresponding":false},{"id":1011753,"name":"Javier García‐Nafría","orcid":"0000-0002-4254-3148","position":8,"is_corresponding":false},{"id":499205,"name":"Stephen R. Sprang","orcid":"0000-0001-6307-6166","position":9,"is_corresponding":false},{"id":1131910,"name":"María José Sánchez-Barrena","orcid":"0000-0002-5986-1804","position":10,"is_corresponding":false},{"id":1011748,"name":"Daniel Muñoz-Reyes","orcid":"0000-0001-8464-1996","position":0,"is_corresponding":true}],"reference_count":75,"raw_metadata":null,"created_at":"2026-07-19T01:15:49.453761Z","pmid":"38018500","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":[]}