Dr. Amir Khan

Summary

The most common cause of inherited Parkinson"s disease is a mutation in Leucine-Rich Repeat Kinase 2 (LRRK2). LRRK2 is implicated in numerous cellular processes including autophagy, mitochondrial dynamics, and ciliogenesis. Despite its importance there is little structural information on LRRK2 signaling pathways. In 2016, Rab GTPases were identified as the first bona fide substrates of LRRK2. Rabs are molecular switches that localize to subcellular compartments and regulate membrane trafficking through recruitment of cytosolic effector proteins. LRRK2 is an effector of Rab29 and is recruited to Golgi where it phosphorylates Rab8a and Rab10. Here we will investigate the molecular basis for the LRRK2 and Rab signaling cascade using X-ray crystallography. The structural basis for Rab29 binding to LRRK2 will be determined. Downstream pathways involving the interactions between phosphorylated Rab8a/10 and phospho-specific effector proteins will be studied using structural and biophysical techniques. Finally, we will investigate the structure and function of PPM1H phosphatase which counters LRRK2 activation by dephosphorylating Rab GTPases. Reversible phosphorylation of Rab GTPases has emerged as a critical regulatory mechanism that is associated with LRRK2 signaling cascades. The project will address fundamental questions on the physiological role of LRRK2 through its regulatory and substrate Rab GTPases.

Funding Agency

Science Foundation Ireland

Programme

Research Frontiers

Person Months

48