{"doi":"10.7554/elife.92536","title":"Redox regulation and dynamic control of brain-selective kinases BRSK1/2 in the AMPK family through cysteine-based mechanisms","abstract":"In eukaryotes, protein kinase signaling is regulated by a diverse array of post-translational modifications, including phosphorylation of Ser/Thr residues and oxidation of cysteine (Cys) residues. While regulation by activation segment phosphorylation of Ser/Thr residues is well understood, relatively little is known about how oxidation of cysteine residues modulate catalysis. In this study, we investigate redox regulation of the AMPK-related brain-selective kinases (BRSK) 1 and 2, and detail how broad catalytic activity is directly regulated through reversible oxidation and reduction of evolutionarily conserved Cys residues within the catalytic domain. We show that redox-dependent control of BRSKs is a dynamic and multilayered process involving oxidative modifications of several Cys residues, including the formation of intramolecular disulfide bonds involving a pair of Cys residues near the catalytic HRD motif and a highly conserved T-loop Cys with a BRSK-specific Cys within an unusual CPE motif at the end of the activation segment. Consistently, mutation of the CPE-Cys increases catalytic activity in vitro and drives phosphorylation of the BRSK substrate Tau in cells. Molecular modeling and molecular dynamics simulations indicate that oxidation of the CPE-Cys destabilizes a conserved salt bridge network critical for allosteric activation. The occurrence of spatially proximal Cys amino acids in diverse Ser/Thr protein kinase families suggests that disulfide-mediated control of catalytic activity may be a prevalent mechanism for regulation within the broader AMPK family.","journal":"eLife","year":2024,"id":487667,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":2,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9499,"is_data_producer":true,"deposit_databanks":{"Dryad":["10.5061/dryad.gb5mkkx1j"]},"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":274583,"name":"Leonard A. Daly","orcid":"0000-0001-9712-9676","position":3,"is_corresponding":false},{"id":1173299,"name":"Sally O. Oswald","orcid":"0009-0002-1307-4482","position":4,"is_corresponding":false},{"id":506210,"name":"Samiksha Katiyar","orcid":"0009-0007-1805-3345","position":5,"is_corresponding":false},{"id":282865,"name":"Aarya Venkat","orcid":"0000-0002-8793-4097","position":6,"is_corresponding":false},{"id":282868,"name":"Wayland Yeung","orcid":"0000-0002-2523-4984","position":7,"is_corresponding":false},{"id":274585,"name":"Claire E. Eyers","orcid":"0000-0002-3223-5926","position":8,"is_corresponding":false},{"id":274588,"name":"Patrick A. Eyers","orcid":"0000-0002-9220-2966","position":9,"is_corresponding":false},{"id":274587,"name":"Natarajan Kannan","orcid":"0000-0002-2833-8375","position":10,"is_corresponding":false},{"id":1173298,"name":"George N. Bendzunas","orcid":"0000-0001-5986-7862","position":0,"is_corresponding":true}],"reference_count":95,"raw_metadata":null,"created_at":"2026-07-19T02:08:10.215754Z","pmid":"40172959","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":[]}