ArticleThe Journal of biological chemistry2019
Parkinson's disease-associated mutations in the GTPase domain of LRRK2 impair its nucleotide-dependent conformational dynamics.
Article in The Journal of biological chemistry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.
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Who cites it
18 citing papers in PubMed, 1 synthesis or guideline pooled it, 31 citations in OpenAlex.
- Molecular Pathways Involved in LRRK2-Linked Parkinson's Disease: A Systematic Review.International journal of molecular sciences · 2022Pooled it
- R1398 is the GTP-γ-phosphate sensor that drives the ROC G-domain switching mechanism unique to Parkinson's disease-associated LRRK2.Research square · 2026Article
- Multi-cohort, cross-species urinary proteomics reveals signatures of LRRK2 dysfunction in Parkinson's disease.Molecular systems biology · 2026Article
- Article
- Structural and biochemical basis of ROC-dependent activation of LRRK2.Research square · 2026Article
- Recent advances in targeting LRRK2 for Parkinson's disease treatment.Journal of translational medicine · 2025Review
- Regulatory imbalance between LRRK2 kinase, PPM1H phosphatase, and ARF6 GTPase disrupts the axonal transport of autophagosomes.Cell reports · 2023Article
- Overview of the Impact of Pathogenic LRRK2 Mutations in Parkinson's Disease.Biomolecules · 2023Review
- Roc, the G-domain of the Parkinson's disease-associated protein LRRK2.Trends in biochemical sciences · 2022Review
- The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity.The Journal of cell biology · 2022Article
- LRRK2 and idiopathic Parkinson's disease.Trends in neurosciences · 2022Review
- Markov State Models and Molecular Dynamics Simulations Provide Understanding of the Nucleotide-Dependent Dimerization-Based Activation of LRRK2 ROC Domain.Molecules (Basel, Switzerland) · 2021Article
- Oligomerization of Lrrk controls actin severing and α-synuclein neurotoxicity in vivo.Molecular neurodegeneration · 2021Article
- The Cell Biology of LRRK2 in Parkinson's Disease.Molecular and cellular biology · 2021Review
- Allosteric inhibition of LRRK2, where are we now.Biochemical Society transactions · 2020Review
- Divergent Effects of G2019S and R1441C LRRK2 Mutations on LRRK2 and Rab10 Phosphorylations in Mouse Tissues.Cells · 2020Article
- Allosteric modulation of the GTPase activity of a bacterial LRRK2 homolog by conformation-specific Nanobodies.The Biochemical journal · 2020Article
- Binding of the Human 14-3-3 Isoforms to Distinct Sites in the Leucine-Rich Repeat Kinase 2.Frontiers in neuroscience · 2020Article
Corrections and comments
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Authors and funding
14 authors at 6 institutions in 2 countries.
Funding
Abstract
Mutation in leucine-rich repeat kinase 2 (LRRK2) is a common cause of familial Parkinson's disease (PD). Recently, we showed that a disease-associated mutation R1441H rendered the GTPase domain of LRRK2 catalytically less active and thereby trapping it in a more persistently "on" conformation. However, the mechanism involved and characteristics of this on conformation remained unknown. Here, we report that the Ras of complex protein (ROC) domain of LRRK2 exists in a dynamic dimer-monomer equilibrium that is oppositely driven by GDP and GTP binding. We also observed that the PD-associated mutations at residue 1441 impair this dynamic and shift the conformation of ROC to a GTP-bound-like monomeric conformation. Moreover, we show that residue Arg-1441 is critical for regulating the conformational dynamics of ROC. In summary, our results reveal that the PD-associated substitutions at Arg-1441 of LRRK2 alter monomer-dimer dynamics and thereby trap its GTPase domain in an activated state.
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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.