Human Molecular Genetics Advance Access published online on June 20, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm151
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Mechanistic insight into the dominant mode of the Parkinson's disease-associated G2019S LRRK2 mutation
1 Institute of Parasitology and Biomedicine "López-Neyra", Spanish National Research Council (CSIC), 18100 Granada, Spain 2 Institute of Biomedicine, Spanish National Research Council (CSIC), 46010 Valencia, Spain
* Senior and Corresponding author: Parque Tecnológico de Ciencias de la Salud Avda del Conocimiento s/n, 18100 Granada, Spain, Tel: +34 958 18 16 54, Fax: +34 958 18 16 32, e-mail: sabine.hilfiker{at}ipb.csic.es
Received April 30, 2007; Revised June 14, 2007; Accepted June 14, 2007
Pathogenic mutations in the leucine-rich repeat kinase-2 (LRRK2) gene cause autosomal-dominant and certain cases of sporadic Parkinson disease. The G2019S substitution in LRRK2 is the most common genetic determinant of Parkinson disease identified so far, and maps to a specific region of the kinase domain called the activation segment. Here we show that autophosphorylation of LRRK2 is an intermolecular reaction and targets two residues within the activation segment. The prominent pathogenic G2019S mutation in LRRK2 results in altered autophosphorylation, and increased autophosphorylation and substrate phosphorylation, through a process that seems to involve reorganization of the activation segment. Our results suggest a molecular mechanistic explanation for how the G2019S mutation enhances the catalytic activity of LRRK2, thereby leading to pathogenicity. These findings have important implications for therapeutic strategies in Parkinson disease.
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