{"doi":"10.1101/2023.12.10.570836","title":"Molecular Determinants and Signaling Effects of PKA RIα Phase Separation","abstract":"Spatiotemporal regulation of intracellular signaling molecules, such as the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), ensures the specific execution of various cellular functions. Liquid-liquid phase separation (LLPS) of the ubiquitously expressed PKA regulatory subunit RIα was recently identified as a major driver of cAMP compartmentation and signaling specificity. However, the molecular determinants of RIα LLPS remain unclear. Here, we reveal that two separate dimerization interfaces combined with the cAMP-induced release of the PKA catalytic subunit (PKA-C) from the pseudosubstrate inhibitory sequence are required to drive RIα condensate formation in cytosol, which is antagonized by docking to A-kinase anchoring proteins. Strikingly, we find that the RIα pseudosubstrate region is critically involved in the formation of a non-canonical R:C complex, which serves to maintain low basal PKA activity in the cytosol by enabling the recruitment of active PKA-C to RIα condensates. Our results suggest that RIα LLPS not only facilitates cAMP compartmentation but also spatially restrains active PKA-C, thus highlighting the functional versatility of biomolecular condensates in driving signaling specificity.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":391152,"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":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9588,"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":1001829,"name":"Emily H. Pool","orcid":"0000-0002-5299-8795","position":1,"is_corresponding":false},{"id":637224,"name":"Jessica Bruystens","orcid":null,"position":2,"is_corresponding":false},{"id":451335,"name":"Xin‐Fu Zhou","orcid":"0000-0002-8687-0175","position":3,"is_corresponding":false},{"id":817892,"name":"Qingrong Li","orcid":"0000-0002-8583-3620","position":4,"is_corresponding":false},{"id":1163911,"name":"Daojia R. Zhou","orcid":null,"position":5,"is_corresponding":false},{"id":1163460,"name":"Max Palay","orcid":"0000-0002-2702-3734","position":6,"is_corresponding":false},{"id":1163912,"name":"Gerald Tan","orcid":null,"position":7,"is_corresponding":false},{"id":1032457,"name":"Lisa Chen","orcid":"0000-0001-6348-4856","position":8,"is_corresponding":false},{"id":1002209,"name":"Jaclyn L.C. Choi","orcid":null,"position":9,"is_corresponding":false},{"id":316472,"name":"Ha Neul Lee","orcid":"0000-0002-2284-4947","position":10,"is_corresponding":false},{"id":326180,"name":"Stefan Strack","orcid":"0000-0002-6175-7280","position":11,"is_corresponding":false},{"id":267377,"name":"Dong Wang","orcid":"0000-0001-5137-0771","position":12,"is_corresponding":false},{"id":232971,"name":"Susan S. Taylor","orcid":"0000-0002-7702-6108","position":13,"is_corresponding":false},{"id":232972,"name":"Sohum Mehta","orcid":"0000-0003-4764-8579","position":14,"is_corresponding":false},{"id":232973,"name":"Jin Zhang","orcid":"0000-0001-7145-7823","position":15,"is_corresponding":false},{"id":1001828,"name":"Julia C. Hardy","orcid":"0000-0002-2693-3437","position":0,"is_corresponding":true}],"reference_count":81,"raw_metadata":null,"created_at":"2026-07-19T01:18:42.653719Z","pmid":"38168176","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":[]}