{"doi":"10.1126/sciadv.adl1258","title":"Discovery of a Cushing’s syndrome protein kinase A mutant that biases signaling through type I AKAPs","abstract":"Adrenal Cushing’s syndrome is a disease of cortisol hypersecretion often caused by mutations in protein kinase A catalytic subunit (PKAc). Using a personalized medicine screening platform, we discovered a Cushing’s driver mutation, PKAc-W196G, in ~20% of patient samples analyzed. Proximity proteomics and photokinetic imaging reveal that PKAc W196G is unexpectedly distinct from other described Cushing’s variants, exhibiting retained association with type I regulatory subunits (RI) and their corresponding A kinase anchoring proteins (AKAPs). Molecular dynamics simulations predict that substitution of tryptophan-196 with glycine creates a 653–cubic angstrom cleft between the catalytic core of PKAc W196G and type II regulatory subunits (RII), but only a 395–cubic angstrom cleft with RI. Endocrine measurements show that overexpression of RIα or redistribution of PKAc W196G via AKAP recruitment counteracts stress hormone overproduction. We conclude that a W196G mutation in the kinase catalytic core skews R subunit selectivity and biases AKAP association to drive Cushing’s syndrome.","journal":"Science Advances","year":2024,"id":436249,"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":0.947,"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":274579,"name":"Dominic P. Byrne","orcid":"0000-0001-5197-345X","position":1,"is_corresponding":false},{"id":274580,"name":"Safal Shrestha","orcid":"0000-0002-9417-2246","position":2,"is_corresponding":false},{"id":831582,"name":"Tyler M. Lakey","orcid":null,"position":3,"is_corresponding":false},{"id":426281,"name":"Kyung‐Soon Lee","orcid":"0000-0003-0859-0554","position":4,"is_corresponding":false},{"id":426279,"name":"Sophia M. Lauer","orcid":"0000-0002-2764-889X","position":5,"is_corresponding":false},{"id":332380,"name":"Kerrie B. Collins","orcid":"0000-0001-9553-1928","position":6,"is_corresponding":false},{"id":274583,"name":"Leonard A. Daly","orcid":"0000-0001-9712-9676","position":7,"is_corresponding":false},{"id":274585,"name":"Claire E. Eyers","orcid":"0000-0002-3223-5926","position":8,"is_corresponding":false},{"id":233081,"name":"Geoffrey S. Baird","orcid":"0000-0001-9064-6558","position":9,"is_corresponding":false},{"id":31807,"name":"Shao‐En Ong","orcid":"0000-0003-3314-5903","position":10,"is_corresponding":false},{"id":274587,"name":"Natarajan Kannan","orcid":"0000-0002-2833-8375","position":11,"is_corresponding":false},{"id":274588,"name":"Patrick A. Eyers","orcid":"0000-0002-9220-2966","position":12,"is_corresponding":false},{"id":320931,"name":"John D. Scott","orcid":"0000-0002-0367-8146","position":13,"is_corresponding":false},{"id":763202,"name":"Mitchell H. Omar","orcid":"0000-0002-1713-4473","position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":null,"created_at":"2026-07-19T02:00:12.706156Z","pmid":"38381834","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":[]}