{"doi":"10.1101/2021.09.29.462278","title":"Two helices control the dynamic crosstalk between the catalytic domains of LRRK2","abstract":"Abstract The two major molecular switches in biology, kinases and GTPases, are both contained in the Parkinson’s Disease-related Leucine-rich repeat kinase 2 (LRRK2). Using hydrogen-deuterium exchange mass spectrometry (HDX-MS) and Molecular Dynamics (MD) simulations, we generated a comprehensive dynamic allosteric portrait of the C-terminal domains of LRRK2 (LRRK2 RCKW ). We identified two helices that shield the kinase domain and regulate LRRK2 conformation and function. One docking helix in COR-B (Dk-Helix) tethers the COR-B domain to the αC helix of the kinase domain and faces its Activation Loop, while the C-terminal helix (Ct-Helix) extends from the WD40 domain and interacts with both kinase lobes. The Ct-Helix and the N-terminus of the Dk-Helix create a “cap” that regulates the N-Lobe of the kinase domain. Our analyses reveal allosteric sites for pharmacological intervention and confirm the kinase domain as the central hub for conformational control.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":221805,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9486,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":349859,"name":"Phillip C. Aoto","orcid":"0000-0001-6518-0899","position":1,"is_corresponding":false},{"id":822352,"name":"Robin Lorenz","orcid":"0000-0002-6425-3790","position":2,"is_corresponding":false},{"id":635994,"name":"Jian Wu","orcid":"0000-0002-8031-9462","position":3,"is_corresponding":false},{"id":590161,"name":"Sven H. Schmidt","orcid":"0000-0001-7666-3482","position":4,"is_corresponding":false},{"id":822353,"name":"Jascha T. Manschwetus","orcid":"0000-0003-3136-9153","position":5,"is_corresponding":false},{"id":822354,"name":"Pallavi Kaila Sharma","orcid":"0000-0003-2986-3515","position":6,"is_corresponding":false},{"id":239980,"name":"Sebastian Mathea","orcid":"0000-0001-8500-4569","position":7,"is_corresponding":false},{"id":239988,"name":"Stefan Knapp","orcid":"0000-0001-5995-6494","position":8,"is_corresponding":false},{"id":349882,"name":"Friedrich W. Herberg","orcid":"0000-0001-7117-7653","position":9,"is_corresponding":false},{"id":232971,"name":"Susan S. Taylor","orcid":"0000-0002-7702-6108","position":10,"is_corresponding":false},{"id":509524,"name":"Jui‐Hung Weng","orcid":"0000-0002-0432-3515","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":null,"created_at":"2026-07-18T23:53:59.302331Z","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":[]}