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Title: Insight into the mode of action of the LRRK2 Y1699C pathogenic mutant
Authors: Daniëls, Veronique
Vancraenenbroeck, Renée
Law, Bernard Mh
Greggio, Elisa
Lobbestael, Evy
Gao, Fangye
De Maeyer, Marc
Cookson, Mark R
Harvey, Kirsten
Baekelandt, Veerle
Taymans, Jean-Marc # ×
Issue Date: Jan-2011
Publisher: Raven Press
Series Title: Journal of Neurochemistry vol:116 issue:2 pages:304-315
Abstract: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most prevalent known cause of autosomal dominant Parkinson's disease (PD). The LRRK2 gene encodes a Roco protein featuring a ROC GTPase and a kinase domain linked by the C-terminal of ROC (COR) domain. Here, we explored the effects of the Y1699C pathogenic LRRK2 mutation in the COR domain on GTPase activity and interactions within the catalytic core of LRRK2. We observed a decrease in GTPase activity for LRRK2 Y1699C comparable to the decrease observed for the R1441C pathogenic mutant and the T1348N dysfunctional mutant. To study the underlying mechanism, we explored the dimerization in the catalytic core of LRRK2. ROC-COR dimerization was significantly weakened by the Y1699C or R1441C/G mutation. Using a competition assay we demonstrated that the intra-molecular ROC:COR interaction is favoured over ROC:ROC dimerization. Interestingly, the intra-molecular ROC:COR interaction was strengthened by the Y1699C mutation. This is supported by a 3D homology model of the ROC-COR tandem of LRRK2, showing that Y1699 is positioned at the intra-molecular ROC:COR interface. In conclusion, our data provides mechanistic insight into the mode of action of the Y1699C LRRK2 mutant: the Y1699C substitution, situated at the intra-molecular ROC:COR interface, strengthens the intra-molecular ROC:COR interaction, thereby locally weakening the dimerization of LRRK2 at the ROC-COR tandem domain resulting in decreased GTPase activity.
URI: 
ISSN: 0022-3042
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Research Group for Neurobiology and Gene Therapy
Biochemistry, Molecular and Structural Biology Section
× corresponding author
# (joint) last author

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