ArticleProceedings of the National Academy of Sciences of the United States of America2019
The dynamic switch mechanism that leads to activation of LRRK2 is embedded in the DFGψ motif in the kinase domain.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 85 citations in OpenAlex.
- Multi-cohort, cross-species urinary proteomics reveals signatures of LRRK2 dysfunction in Parkinson's disease.Molecular systems biology · 2026Article
- Article
- Regulation of LRRK2 activity by metabolic stress and heavy metal exposure.Brain research · 2025Article
- Cryo-electron tomography reveals the microtubule-bound form of inactive LRRK2.bioRxiv : the preprint server for biology · 2025Article
- Role of LRRK2 in axonal transport and Parkinson's disease.The Biochemical journal · 2025Review
- The design and development of LRRK2 inhibitors as novel therapeutics for Parkinson's disease.Future medicinal chemistry · 2025Review
- LRRK2 Kinase Inhibitor PF-06447475 Protects Drosophila melanogaster against Paraquat-Induced Locomotor Impairment, Life Span Reduction, and Oxidative Stress.Neurochemical research · 2024Article
- RedOx regulation of LRRK2 kinase activity by active site cysteines.NPJ Parkinson's disease · 2024Article
- Role of the leucine-rich repeat protein kinase 2 C-terminal tail in domain cross-talk.The Biochemical journal · 2024Article
- Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2.Science (New York, N.Y.) · 2023Article
- Targeting the Cysteine Redox Proteome in Parkinson's Disease: The Role of Glutathione Precursors and Beyond.Antioxidants (Basel, Switzerland) · 2023Review
- Capturing Differences in the Regulation of LRRK2 Dynamics and Conformational States by Small Molecule Kinase Inhibitors.ACS chemical biology · 2023Article
- Neuroprotective actions of a fatty acid nitroalkene in Parkinson's disease.NPJ Parkinson's disease · 2023Article
- LRRK2 Structure-Based Activation Mechanism and Pathogenesis.Biomolecules · 2023Review
- Regulators of proteostasis are translationally repressed in fibroblasts from patients with sporadic and LRRK2-G2019S Parkinson's disease.NPJ Parkinson's disease · 2023Article
- Calculation of centralities in protein kinase A.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Mucosal Immunity and the Gut-Microbiota-Brain-Axis in Neuroimmune Disease.International journal of molecular sciences · 2022Review
- Impact of 100 LRRK2 variants linked to Parkinson's disease on kinase activity and microtubule binding.The Biochemical journal · 2022Article
- LRRK2 and Proteostasis in Parkinson's Disease.International journal of molecular sciences · 2022Review
- The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity.The Journal of cell biology · 2022Article
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
Leucine-rich repeat kinase 2 (LRRK2) is a large multidomain protein, and LRRK2 mutants are recognized risk factors for Parkinson's disease (PD). Although the precise mechanisms that control LRRK2 regulation and function are unclear, the importance of the kinase domain is strongly implicated, since 2 of the 5 most common familial LRRK2 mutations (G2019S and I2020T) are localized to the conserved DFGψ motif in the kinase core, and kinase inhibitors are under development. Combining the concept of regulatory (R) and catalytic (C) spines with kinetic and cell-based assays, we discovered a major regulatory mechanism embedded within the kinase domain and show that the DFG motif serves as a conformational switch that drives LRRK2 activation. LRRK2 is quite unusual in that the highly conserved Phe in the DFGψ motif, which is 1 of the 4 R-spine residues, is replaced with tyrosine (DY
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.