Leucine-rich repeat kinase 2 (LRRK2) is a 286-kDa enzyme. It functions as a dimer in vivo. Mutations in LRRK2 have been associated with Parkinson’s disease (PD), and clustering of these mutations in the catalytic core of the multidomain protein suggests that disease is linked to altered enzymatic activity.
This project focuses on the structural elucidation of LRRK2.
Parkinson´s disease (PD) is one the most common neurodegenerative movement disorders. Although treatments are available to lessen the symptoms, a complete cure is still missing. Several genes have been genetically linked to inherited forms of PD and the study of these gene products is expected to reveal crucial insights into the pathobiology of PD. The most prevalent is leucine rich repeat kinase 2 (LRRK2).
LRRK2 is a member of the ROCO protein family. It has protein-protein interaction domains including armadillo, leucine-rich and ankyrin repeats, and a catalytic core formed by a GTPase and a kinase. Most of the pathologically important LRRK2 mutations are clustered in the catalytic core of the protein, hinting that altered GTPase and kinase activities play a crucial role in pathogenesis. The LRRK2 pathway is currently regarded as one of the most promising drug targets.
We are working to obtain structural insights of LRRK2.