{"doi":"10.1016/j.tibs.2021.10.003","title":"Closing the structure-to-function gap for LRRK2","abstract":"Variations in the LRRK2 gene represent one of the strongest genetic factors for Parkinson's disease (PD). It has become clear that structural knowledge of the encoded large multidomain LRRK2 protein will cast light on its biological function. The new study from Myasnikov, Zhu, et al. provides a high-resolution structure of the full-length LRRK2. Variations in the LRRK2 gene represent one of the strongest genetic factors for Parkinson's disease (PD). It has become clear that structural knowledge of the encoded large multidomain LRRK2 protein will cast light on its biological function. The new study from Myasnikov, Zhu, et al. provides a high-resolution structure of the full-length LRRK2. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of autosomal dominant PD [1.Paisan-Ruiz C. et al.Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease.Neuron. 2004; 44: 595-600Abstract Full Text Full Text PDF PubMed Scopus (1852) Google Scholar,2.Zimprich A. et al.Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology.Neuron. 2004; 44: 601-607Abstract Full Text Full Text PDF PubMed Scopus (2231) Google Scholar]. In addition, genetic studies support a role for LRRK2 in the pathogenesis of sporadic PD [3.Nalls M.A. et al.Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies.Lancet Neurol. 2019; 18: 1091-1102Abstract Full Text Full Text PDF PubMed Scopus (595) Google Scholar], providing a solid justification for studying LRRK2-driven mechanisms to understand PD more broadly.LRRK2 is a large protein with several protein–protein interaction domains and a central enzymatic region. The Ras of complex (ROC) GTPase protein domain and the kinase (KIN) domain, linked by the carboxy-terminal of ROC (COR) sequence, define the enzymatic core of the protein (Figure 1, top left); this is also where all the known disease-causing mutations are concentrated [4.Berwick D.C. et al.LRRK2 Biology from structure to dysfunction: research progresses, but the themes remain the same.Mol. Neurogener. 2019; 14: 49Crossref PubMed Scopus (60) Google Scholar]. LRRK2 pathogenic mutations lead to increased kinase activity, and the location of the most common G2019S mutation in the kinase activation loop could explain the hyperactivity of the kinase. However, the explanation is not as straightforward for mutations found in the ROC and COR domains. As such, a high-resolution LRRK2 structure is poised to provide insights into the functions of the individual domains, their functional interplay, and the impact of the pathogenic mutations on these processes.Initial attempts to resolve the atomic structure of LRRK2 were based on smaller fragments of the protein and by reference to orthologous proteins [5.Deng J. et al.Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase.Proc. Natl. Acad. Sci. U. S. A. 2008; 105: 1499-1504Crossref PubMed Scopus (190) Google Scholar]. A clearer picture began to emerge when Villa and colleagues combined integrative modeling with in situ cryo-electron tomography (cryo-ET) and cryo-correlative light microscopy to provide a 14 Å structure of microtubule-associated LRRK2 filaments [6.Watanabe R. et al.The in situ structure of Parkinson's disease-linked LRRK2.Cell. 2020; 182: 1508-1518Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar]. Complementary pioneering work reported a 3.5 Å cryo-electron microscopy (cryo-EM) structure of LRRK2 containing the C-terminal ROC, COR, KIN, and WD40 domains, referred to as LRRK2RCKW [7.Deniston C.K. et al.Structure of LRRK2 in Parkinson's disease and model for microtubule interaction.Nature. 2020; 588: 344-349Crossref PubMed Scopus (67) Google Scholar]. These combined technical achievements illustrated the power of orthogonal approaches to understanding L","journal":"Trends in Biochemical Sciences","year":2021,"id":199493,"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":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9103,"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":322654,"name":"Chuyu Chen","orcid":"0000-0001-5666-5173","position":1,"is_corresponding":false},{"id":322658,"name":"Loukia Parisiadou","orcid":"0000-0002-2569-4200","position":2,"is_corresponding":false},{"id":775998,"name":"Valerie Tokars","orcid":"0000-0002-2619-3969","position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":null,"created_at":"2026-07-18T23:50:40.558460Z","pmid":"34756665","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":[]}