Mechanistic insight into the dominant mode of the Parkinson's disease-associated G2019S LRRK2 mutation

Abstract

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.

Roco kinase structures give insights into the mechanism of Parkinson disease-related leucine-rich-repeat kinase 2 mutations

“…The most prevalent PD mutation is G2019S in the kinase domain, which enhances kinase activity, whereas the PD-related mutation I2020T shows slightly decreased activity (15,16,(28)(29)(30). The LRRK2 G2019 and I2020 residues are conserved in Roco4 and correspond to G1179 and L1180, respectively (Fig.…”

“…LRRK2, and most likely all Roco proteins, are dimer in solutions using the COR domain as dimerization interface (12,13,27). Autophosphorylation is essential for the function of LRRK2; however, data for autophosphorylation both in cis and in trans have been reported (15,27). The recent structure of Aurora2 shows that the αC-helix is part of the kinase dimerization interface (31); because LRRK2 autophosphorylation can occur in trans (15), the R1918A mutation may disturb the putative dimer interface and subsequently reduce kinase activity.…”

“…LRRK2 kinase activity is linked critically to clinical effects, and several pathogenic mutations in LRRK2 result in enhanced kinase activity, suggesting a possible PD-related gain of abnormal or toxic function (14)(15)(16). However, because of the lack of sufficient recombinant protein and physiological substrate, the published data regarding kinase activity of the PD-related mutants are conflicting (except for G2019S, which is associated consistently with an increased kinase activity) (17,18).…”

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

“…1) [31,66]. A 2-3-fold increase in kinase activity of G2019S LRRK2 compared with wild-type protein has been consistently seen by many groups [12,13,15,20,56,[67][68][69][70][71][72][73].…”

Update on the functional biology of Lrrk2

“…Since then, the G2019S mutation has been reported to enhance kinase activity compared with WT activity [45,47,55,56]. The I2020T mutation has been reported to increase kinase activity [44,57] but also to reduce kinase activity [55].…”