ArticleThe Journal of biological chemistry2014
The Parkinson disease-linked LRRK2 protein mutation I2020T stabilizes an active state conformation leading to increased kinase activity.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 47 citations in OpenAlex.
- Widespread distribution of α-synuclein oligomers in LRRK2-related Parkinson's disease.Acta neuropathologica · 2025Article
- Exploring LRRK2-dependent Mechanisms in Parkinson's Disease Therapy.CNS & neurological disorders drug targets · 2025Review
- Analysis of rare Parkinson's disease variants in millions of people.NPJ Parkinson's disease · 2024Article
- Emerging perspectives on precision therapy for Parkinson's disease: multidimensional evidence leading to a new breakthrough in personalized medicine.Frontiers in aging neuroscience · 2024Review
- Topological analysis as a tool for detection of abnormalities in protein-protein interaction data.Bioinformatics (Oxford, England) · 2022Article
- LRRK2 and idiopathic Parkinson's disease.Trends in neurosciences · 2022Review
- Development of mutation-selective LRRK2 kinase inhibitors as precision medicine for Parkinson's disease and other diseases for which carriers are at increased risk.Frontiers in neurology · 2022Article
- Genetic and Environmental Factors Influence the Pleomorphy ofInternational journal of molecular sciences · 2021Review
- Review
- Article
- The dynamic switch mechanism that leads to activation of LRRK2 is embedded in the DFGψ motif in the kinase domain.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- LRRK 2 gene mutations in the pathophysiology of the ROCO domain and therapeutic targets for Parkinson's disease: a review.Journal of biomedical science · 2018Review
- LRRK2 regulates retrograde synaptic compensation at the Drosophila neuromuscular junction.Nature communications · 2016Article
- LRRK2 autophosphorylation enhances its GTPase activity.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2016Article
- Decoding Parkinson's Disease Pathogenesis: The Role of Deregulated mRNA Translation.Journal of Parkinson's disease · 2016Review
- Cellular processes associated with LRRK2 function and dysfunction.The FEBS journal · 2015Review
- LRRK2 Pathways Leading to Neurodegeneration.Current neurology and neuroscience reports · 2015Review
- Ten years and counting: moving leucine-rich repeat kinase 2 inhibitors to the clinic.Movement disorders : official journal of the Movement Disorder Society · 2015Review
- LRRK2 pathobiology in Parkinson's disease.Journal of neurochemistry · 2014Review
- Unique functional and structural properties of the LRRK2 protein ATP-binding pocket.The Journal of biological chemistry · 2014Article
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
The effect of leucine-rich repeat kinase 2 (LRRK2) mutation I2020T on its kinase activity has been controversial, with both increased and decreased effects being reported. We conducted steady-state and pre-steady-state kinetic studies on LRRKtide and its analog LRRKtide(S). Their phosphorylation differs by the rate-limiting steps: product release is rate-limiting for LRRKtide and phosphoryl transfer is rate-limiting for LRRKtide(S). As a result, we observed that the I2020T mutant is more active than wild type (WT) LRRK2 for LRRKtide(S) phosphorylation, whereas it is less active than WT for LRRKtide phosphorylation. Our pre-steady-state kinetic data suggest that (i) the I2020T mutant accelerates the rates of phosphoryl transfer of both reactions by 3-7-fold; (ii) this increase is masked by a rate-limiting product release step for LRRKtide phosphorylation; and (iii) the observed lower activity of the mutant for LRRKtide phosphorylation is a consequence of its instability: the concentration of the active form of the mutant is 3-fold lower than WT. The I2020T mutant has a dramatically low KATP and therefore leads to resistance to ATP competitive inhibitors. Two well known DFG-out or type II inhibitors are also weaker toward the mutant because they inhibit the mutant in an unexpected ATP competitive mechanism. The I2020 residue lies next to the DYG motif of the activation loop of the LRRK2 kinase domain. Our modeling and metadynamic simulations suggest that the I2020T mutant stabilizes the DYG-in active conformation and creates an unusual allosteric pocket that can bind type II inhibitors but in an ATP competitive fashion.
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