ArticlePLoS biology2022
LRRK2 dynamics analysis identifies allosteric control of the crosstalk between its catalytic domains.
Article in PLoS biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 25 citations in OpenAlex.
- Constrained peptide mimics of the LRRK2 C-terminal Helix inhibits its kinase activity.Bioorganic chemistry · 2026Article
- LRRK2: Molecular Mechanisms in Parkinson's Disease.International journal of molecular sciences · 2026Review
- Correction: LRRK2 dynamics analysis identifies allosteric control of the crosstalk between its catalytic domains.PLoS biology · 2025Article
- Molecular dynamics studies reveal the structural impacts of LRRK2 R1441C and LRRK2 D1994A mutations in Parkinson's disease.Biochemistry and biophysics reports · 2024Article
- LRRK2 in Parkinson's disease: upstream regulation and therapeutic targeting.Trends in molecular medicine · 2024Review
- Role of the leucine-rich repeat protein kinase 2 C-terminal tail in domain cross-talk.The Biochemical journal · 2024Article
- Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM.Cell discovery · 2024Article
- Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2.Science (New York, N.Y.) · 2023Article
- Structure and regulation of full-length human leucine-rich repeat kinase 1.Nature communications · 2023Article
- Capturing the domain crosstalk in full length LRRK2 and LRRK2RCKW.The Biochemical journal · 2023Article
- Capturing Differences in the Regulation of LRRK2 Dynamics and Conformational States by Small Molecule Kinase Inhibitors.ACS chemical biology · 2023Article
- LRRK2 Structure-Based Activation Mechanism and Pathogenesis.Biomolecules · 2023Review
- Protein kinase C showcases allosteric control: activation of LRRK1.The Biochemical journal · 2023Article
- Roc, the G-domain of the Parkinson's disease-associated protein LRRK2.Trends in biochemical sciences · 2022Review
- PKC isoforms activate LRRK1 kinase by phosphorylating conserved residues (Ser1064, Ser1074 and Thr1075) within the CORB GTPase domain.The Biochemical journal · 2022Article
- Impact of 100 LRRK2 variants linked to Parkinson's disease on kinase activity and microtubule binding.The Biochemical journal · 2022Article
- The Double-Faceted Role of Leucine-Rich Repeat Kinase 2 in the Immunopathogenesis of Parkinson's Disease.Frontiers in aging neuroscience · 2022Review
Corrections and comments
- Erratum issued
Authors and funding
13 authors at 3 institutions in 2 countries.
Funding
Abstract
The 2 major molecular switches in biology, kinases and GTPases, are both contained in the Parkinson disease-related leucine-rich repeat kinase 2 (LRRK2). Using hydrogen-deuterium exchange mass spectrometry (HDX-MS) and molecular dynamics (MD) simulations, we generated a comprehensive dynamic allosteric portrait of the C-terminal domains of LRRK2 (LRRK2RCKW). We identified 2 helices that shield the kinase domain and regulate LRRK2 conformation and function. One helix in COR-B (COR-B Helix) tethers the COR-B domain to the αC helix of the kinase domain and faces its activation loop, while the C-terminal helix (Ct-Helix) extends from the WD40 domain and interacts with both kinase lobes. The Ct-Helix and the N-terminus of the COR-B Helix create a "cap" that regulates the N-lobe of the kinase domain. Our analyses reveal allosteric sites for pharmacological intervention and confirm the kinase domain as the central hub for conformational control.
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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.