ArticleThe Journal of biological chemistry2009
Dependence of leucine-rich repeat kinase 2 (LRRK2) kinase activity on dimerization.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 103 papers.
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Who cites it
103 citing papers in PubMed, 181 citations in OpenAlex.
- Regulation between LRRK2 and PP2A signaling in cellular models of Parkinson's disease.The Biochemical journal · 2026Article
- LRRK2 in Parkinson's disease: upstream regulation and therapeutic targeting.Trends in molecular medicine · 2024Review
- VIK-Mediated Auxin Signaling Regulates Lateral Root Development in Arabidopsis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Cell-autonomous role of leucine-rich repeat kinase in the protection of dopaminergic neuron survival.eLife · 2024Article
- Leucine-rich repeat kinase 2 at a glance.Journal of cell science · 2023Article
- Doubly Constrained C-terminal of Roc (COR) Domain-Derived Peptides Inhibit Leucine-Rich Repeat Kinase 2 (LRRK2) Dimerization.ACS chemical neuroscience · 2023Article
- LRRK2 and Parkinson's disease: from genetics to targeted therapy.Annals of clinical and translational neurology · 2023Review
- The Relationship between Iron and LRRK2 in a 6-OHDA-Induced Parkinson's Disease Model.International journal of molecular sciences · 2023Article
- Article
- Nanobodies as allosteric modulators of Parkinson's disease-associated LRRK2.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Structural Biology of LRRK2 and its Interaction with Microtubules.Movement disorders : official journal of the Movement Disorder Society · 2021Review
- LRRK2 Targeting Strategies as Potential Treatment of Parkinson's Disease.Biomolecules · 2021Review
- Oligomerization of Lrrk controls actin severing and α-synuclein neurotoxicity in vivo.Molecular neurodegeneration · 2021Article
- Review
- Pathogenic LRRK2 requires secondary factors to induce cellular toxicity.Bioscience reports · 2020Article
- Fluctuation Imaging of LRRK2 Reveals that the G2019S Mutation Alters Spatial and Membrane Dynamics.Molecules (Basel, Switzerland) · 2020Article
- Allosteric modulation of the GTPase activity of a bacterial LRRK2 homolog by conformation-specific Nanobodies.The Biochemical journal · 2020Article
- Advances in elucidating the function of leucine-rich repeat protein kinase-2 in normal cells and Parkinson's disease.Current opinion in cell biology · 2020Review
- Comparative Genomic Mapping Implicates LRRK2 for Intellectual Disability and Autism at 12q12, and HDHD1, as Well as PNPLA4, for X-Linked Intellectual Disability at Xp22.31.Journal of clinical medicine · 2020Article
- LRRK2 and the Endolysosomal System in Parkinson's Disease.Journal of Parkinson's disease · 2020Review
43 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Dominant missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common known genetic cause of Parkinson disease. LRRK2 encodes a serine/threonine protein kinase, and pathogenic mutations may increase kinase activity. Intrinsic GTP binding in the GTPase domain may govern kinase activity through an internal signal transduction cascade. As with many protein kinases, LRRK2 self-interacts through mechanisms that may regulate enzymatic activity. We find that the disruption of either GTPase or kinase activity enhances the formation of high molecular weight oligomers and prevents the formation of LRRK2 dimer structures. In addition, brief application of the broad spectrum kinase inhibitor staurosporine ablates LRRK2 dimers and promotes LRRK2 high molecular weight oligomers. LRRK2 interactions with other proteins in cell lines are kinase-independent and include chaperones and cell cytoskeleton components, suggesting that LRRK2 self-assembly principally dictates complex size. To further explore the mechanics of kinase activation, we separate soluble LRRK2 protein that encodes the pathogenic G2019S mutation into high molecular weight oligomers, dimers, and monomers and find that kinase activity resides with dimeric LRRK2. Some PD-associated mutations that increase kinase activity in vitro significantly increase the proportion of dimer structures relative to total LRRK2 protein, providing additional insight into how pathogenic mutations may alter normal enzymatic regulation. Targeting and tracking LRRK2 dimerization may provide a clear way to observe LRRK2 kinase activity in living cells, and disruption of dimeric LRRK2 through kinase inhibition or other means may attenuate pathogenic increases in LRRK2 enzymatic output.
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Registered trials
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.