Malfunctioning of the protein leucine-rich repeat kinase 2 (LRRK2) is a common genetic cause of Parkinson’s disease (PD). LRRK2 is a very large and complex protein, and insight into the exact function of this protein can help devise an effective strategy to develop novel drugs. Nanobodies are small, stable protein fragments derived from a special type of antibodies that form excellent tools to examine such complex dynamic proteins. We previously identified nanobodies targeting LRRK2.
A full biochemical and structural characterization of these nanobodies will be crucial to guide their development into tools to probe the structure, function and biology of LRRK2.
Nanobodies bind to their target proteins with a range of different affinities and specificities. Moreover, the binding affinity of a nanobody for LRRK2 can also depend on the 3-dimensional conformation of LRRK2. Using a variety of biochemical and biophysical methods we will investigate how strong the nanobodies bind to LRRK2 and we will study their influence on LRRK2 activity. Finally, using techniques that allow to resolve the three-dimensional structure of proteins up to atomic details, we will visualize how and where exactly the nanobodies bind.
Next Steps for Development:
The full biochemical and structural characterization of LRRK2 nanobodies as envisioned in this project will be used to develop these nanobodies into very potent instruments to study the structure and mechanism of LRRK2 in vitro, which can subsequently be used to discover new drugs targeting LRRK2. Moreover, we will also use these nanobodies as tools to study the distribution, functioning and biology of LRRK2 in cells and in vivo.