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 full length LRRK2. A high-resolution structure of wild-type LRRK2 would lay the foundations for drug discovery and development.
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.
Biochemical experiments suggest that LRRK2 kinase activity may be regulated by dimerization, but a high resolution structure of the complex formed by the full-length protein is still lacking. This would reveal the motif organization and help to elucidate how LRRK2 kinase activity is regulated at the molecular level.
We are working to obtain the structure of the dimeric wild-type LRRK2 protein complex by cryo-EM and single particle analysis. A high resolution map will allow the known atomic structures of the motifs to be reliably docked, providing insight into the domain organization of full length LRRK2. Further, efforts to enhance sample quality and the integrity of the whole complex are underway to aid high resolution data collection by cryo-EM.