Mechanistic insight into the dominant mode of the Parkinson's disease-associated G2019S LRRK2 mutation.
Pathogenic mutations in the leucine-rich repeat kinase-2 (LRRK2) gene cause autosomal-dominant and certain cases of sporadic Parkinson's disease (PD). The G2019S substitution in LRRK2 is the most common genetic determinant of PD 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 PD.
Luzón-Toro
Berta
B
Institute of Parasitology and Biomedicine, Lopez-Neyra, Spanish National Research Council, Granada, Spain.
Rubio de la Torre
Elena
E
Delgado
Asunción
A
Pérez-Tur
Jordi
J
Hilfiker
Sabine
S
D000595:Amino Acid Sequence; D002384:Catalysis; D004252:DNA Mutational Analysis; D020022:Genetic Predisposition to Disease; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism
D011994:Recombinant Proteins; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases