The WD40 domain is required for LRRK2 neurotoxicity

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson disease (PD). LRRK2 contains an "enzymatic core" composed of GTPase and kinase domains that is flanked by leucine-rich repeat (LRR) and WD40 protein-protein interaction domains. While kinase ac...

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Bibliographic Details
Published in:PloS one 2009-12, Vol.4 (12), p.e8463
Main Authors: Jorgensen, Nathan D, Peng, Yong, Ho, Cherry C-Y, Rideout, Hardy J, Petrey, Donald, Liu, Peng, Dauer, William T
Format: Article
Language:English
Subjects:
Acids
Animals
Apoptosis
Biochemistry
Biology
Biophysics
Cell death
Cell Line
Complex formation
Dimerization
Enzymes
Guanosine triphosphatases
Guanosine triphosphate
Humans
Kinases
Leucine
LRRK2 protein
Mice
Models, Molecular
Molecular Weight
Movement disorders
Mutation
Neurodegeneration
Neurodegenerative diseases
Neurological Disorders
Neurological Disorders/Alzheimer Disease
Neurological Disorders/Movement Disorders
Neurological Disorders/Neurogenetics
Neurology
Neurotoxicity
Neurotoxins - chemistry
Neurotoxins - toxicity
Parkinson disease
Parkinson's disease
Phosphorylation
Phosphorylation - drug effects
Protein interaction
Protein Multimerization - drug effects
Protein Structure, Tertiary
Protein-protein interactions
Protein-Serine-Threonine Kinases - chemistry
Protein-Serine-Threonine Kinases - toxicity
Proteins
Sequence Deletion
Structural Homology, Protein
Structure-Activity Relationship
Trends
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Description
Summary:Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson disease (PD). LRRK2 contains an "enzymatic core" composed of GTPase and kinase domains that is flanked by leucine-rich repeat (LRR) and WD40 protein-protein interaction domains. While kinase activity and GTP-binding have both been implicated in LRRK2 neurotoxicity, the potential role of other LRRK2 domains has not been as extensively explored. We demonstrate that LRRK2 normally exists in a dimeric complex, and that removing the WD40 domain prevents complex formation and autophosphorylation. Moreover, loss of the WD40 domain completely blocks the neurotoxicity of multiple LRRK2 PD mutations. These findings suggest that LRRK2 dimerization and autophosphorylation may be required for the neurotoxicity of LRRK2 PD mutations and highlight a potential role for the WD40 domain in the mechanism of LRRK2-mediated cell death.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0008463