Modelling LRRK2 Structure and Characterizing the LRRK2 Activation Cycle in LRRK2-mediated Parkinson's disease
Research Grant, 2016
Promising Outcomes of Original Grant:
We modelled the three-dimensional structure of full-length leucine rich repeat kinase 2 (LRRK2) using a mixed approach, combining protein models with experimental restraints provided by chemical crosslinking (chemically joining two or more molecules), electron microscopy (technique that produces high resolution images) and small-angle X-ray scattering (technique to study the shape of molecules); the resulting model suggests compact folding of LRRK2 with multiple domain-domain contacts (how a protein is assembled). Together with biochemical data, it provides novel insight into the regulation of LRRK2 kinase activity (protein regulation), revealing an essential role of LRRK2 in the crosstalk between the Ras-of-complex proteins (Roc) G-domain and the kinase domain. Furthermore, our data demonstrate that, in contrast to Ras-like small G-proteins (also called GTPases), LRRK2 forms dimers (two molecules linked together) and its kinase activity is regulated by the Roc domain, suggesting that Roco proteins form a different class of G-proteins.
Objectives for Supplemental Investigation:
Mutations in the LRRK2 gene are associated with Parkinson's disease (PD). Although the function of LRRK2 is not fully understood, inhibitors of LRRK2 kinase activity could potentially be used to prevent or treat PD. Identifying and developing LRRK2-specific compounds is difficult but can be greatly facilitated by understanding the three-dimensional structure of LRRK2. Furthermore, understanding the interaction of different domains (key sites on a protein) in the LRRK2 structure is of fundamental importance for the mechanistic understanding of this protein. Taking advantage of the expertise within the larger LRRK2 biology consortium, the team aims at describing the first multi-domain model for LRRK2 to provide insights into the molecular activation mechanisms as well as the impact of PD mutations on a structural level.
Importance of This Research for the Development of a New PD Therapy:
Mutations in the LRRK2 protein associated with PD may increase the kinase activity of this enzyme; if this is true, LRRK2 inhibitors could be used to treat or prevent PD. Identifying and developing small molecules that inhibit LRRK2 but no other essential kinases is difficult. Therefore, to generate safe drugs for disease treatment, compounds targeting molecular structures beyond the kinase domain might be of importance. We hope to enable the discovery and development of PD therapeutics by obtaining the first high-resolution structural model for the protein LRRK2 and by understanding fundamental aspects of its molecular activation mechanisms.
Associate Professor at University of Groningen
Location: Groningen, Netherlands
Group Leader at German Center for Neurodegenerative Diseases (DZNE)
Location: Tubingen, Germany