{"doi":"10.1101/2020.01.06.895367","title":"Parkinson’s Disease-linked LRRK2 structure and model for microtubule interaction","abstract":"Abstract L eucine R ich R epeat K inase 2 ( LRRK2 ) is the most commonly mutated gene in familial Parkinson’s disease. LRRK2 is proposed to function in membrane trafficking and co-localizes with microtubules. We report the 3.5Å structure of the catalytic half of LRRK2, and an atomic model of microtubule-associated LRRK2 built using a reported 14Å cryo-electron tomography in situ structure. We propose that the conformation of LRRK2’s kinase domain regulates its microtubule interaction, with a closed conformation favoring binding. We show that the catalytic half of LRRK2 is sufficient for microtubule binding and blocks the motility of the microtubule-based motors kinesin and dynein in vitro . Kinase inhibitors that stabilize an open conformation relieve this interference and reduce LRRK2 filament formation in cells, while those that stabilize a closed conformation do not. Our findings suggest that LRRK2 is a roadblock for microtubule-based motors and have implications for the design of therapeutic LRRK2 kinase inhibitors.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":119352,"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":21,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9446,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":239979,"name":"John Salogiannis","orcid":"0000-0002-1988-7284","position":1,"is_corresponding":false},{"id":239980,"name":"Sebastian Mathea","orcid":"0000-0001-8500-4569","position":2,"is_corresponding":false},{"id":239981,"name":"David Snead","orcid":"0000-0001-7839-452X","position":3,"is_corresponding":false},{"id":239982,"name":"Indrajit Lahiri","orcid":"0000-0002-5633-7978","position":4,"is_corresponding":false},{"id":239984,"name":"Oscar Donosa","orcid":"0000-0002-1871-447X","position":5,"is_corresponding":false},{"id":239985,"name":"Reika Watanabe","orcid":"0000-0002-7427-7702","position":6,"is_corresponding":false},{"id":239986,"name":"Jan Böhning","orcid":"0000-0002-6242-1041","position":7,"is_corresponding":false},{"id":239987,"name":"Andrew K. Shiau","orcid":"0000-0002-3993-4842","position":8,"is_corresponding":false},{"id":554149,"name":"Stefan Knapp","orcid":"0000-0002-0604-9185","position":9,"is_corresponding":false},{"id":98028,"name":"Elizabeth Villa","orcid":"0000-0003-4677-9809","position":10,"is_corresponding":false},{"id":239989,"name":"Samara L. Reck‐Peterson","orcid":"0000-0002-1553-465X","position":11,"is_corresponding":false},{"id":239990,"name":"Andrés E. Leschziner","orcid":"0000-0002-7732-7023","position":12,"is_corresponding":false},{"id":554148,"name":"Colin Deniston","orcid":"0000-0002-0204-0466","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-18T23:14:08.313144Z","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":[]}