ArticlePloS one2010
Identification and characterization of a leucine-rich repeat kinase 2 (LRRK2) consensus phosphorylation motif.
Article in PloS one, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 71 citations in OpenAlex.
- Selectivity profiles and substrate recognition of Rab-phosphorylating kinases.The Biochemical journal · 2025Article
- The Leucine-Rich Repeat Kinase 2 Variant LRRK2International journal of molecular sciences · 2025Article
- Targeting leucine-rich repeat serine/threonine-protein kinase 2 sensitizes pancreatic ductal adenocarcinoma to anti-PD-L1 immunotherapy.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Article
- Overview of the Impact of Pathogenic LRRK2 Mutations in Parkinson's Disease.Biomolecules · 2023Review
- LRRK2 dynamics analysis identifies allosteric control of the crosstalk between its catalytic domains.PLoS biology · 2022Article
- Structural Biology of LRRK2 and its Interaction with Microtubules.Movement disorders : official journal of the Movement Disorder Society · 2021Review
- Article
- LRRK2 Phosphorylation, More Than an Epiphenomenon.Frontiers in neuroscience · 2020Review
- Kinase Domain Is a Dynamic Hub for Driving LRRK2 Allostery.Frontiers in molecular neuroscience · 2020Article
- Pharmacodynamic Biomarkers for Emerging LRRK2 Therapeutics.Frontiers in neuroscience · 2020Review
- Binding of the Human 14-3-3 Isoforms to Distinct Sites in the Leucine-Rich Repeat Kinase 2.Frontiers in neuroscience · 2020Article
- Physiological and pathological functions of LRRK2: implications from substrate proteins.Neuronal signaling · 2018Review
- GTP binding regulates cellular localization of Parkinson's disease-associated LRRK2.Human molecular genetics · 2017Article
- Human R1441C LRRK2 regulates the synaptic vesicle proteome and phosphoproteome in a Drosophila model of Parkinson's disease.Human molecular genetics · 2016Article
- Activation of FADD-Dependent Neuronal Death Pathways as a Predictor of Pathogenicity for LRRK2 Mutations.PloS one · 2016Article
- Protective LRRK2 R1398H Variant Enhances GTPase and Wnt Signaling Activity.Frontiers in molecular neuroscience · 2016Article
- G2385R and I2020T Mutations Increase LRRK2 GTPase Activity.BioMed research international · 2016Article
- Leucine-Rich Repeat Kinase 2 (LRRK2) phosphorylates p53 and induces p21(WAF1/CIP1) expression.Molecular brain · 2015Article
- LRRK2 G2019S mutation attenuates microglial motility by inhibiting focal adhesion kinase.Nature communications · 2015Article
- Cellular processes associated with LRRK2 function and dysfunction.The FEBS journal · 2015Review
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
Mutations in LRRK2 (leucine-rich repeat kinase 2) have been identified as major genetic determinants of Parkinson's disease (PD). The most prevalent mutation, G2019S, increases LRRK2's kinase activity, therefore understanding the sites and substrates that LRRK2 phosphorylates is critical to understanding its role in disease aetiology. Since the physiological substrates of this kinase are unknown, we set out to reveal potential targets of LRRK2 G2019S by identifying its favored phosphorylation motif. A non-biased screen of an oriented peptide library elucidated F/Y-x-T-x-R/K as the core dependent substrate sequence. Bioinformatic analysis of the consensus phosphorylation motif identified several novel candidate substrates that potentially function in neuronal pathophysiology. Peptides corresponding to the most PD relevant proteins were efficiently phosphorylated by LRRK2 in vitro. Interestingly, the phosphomotif was also identified within LRRK2 itself. Autophosphorylation was detected by mass spectrometry and biochemical means at the only F-x-T-x-R site (Thr 1410) within LRRK2. The relevance of this site was assessed by measuring effects of mutations on autophosphorylation, kinase activity, GTP binding, GTP hydrolysis, and LRRK2 multimerization. These studies indicate that modification of Thr1410 subtly regulates GTP hydrolysis by LRRK2, but with minimal effects on other parameters measured. Together the identification of LRRK2's phosphorylation consensus motif, and the functional consequences of its phosphorylation, provide insights into downstream LRRK2-signaling pathways.
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