TY - JOUR AU - AB -

Leucine Rich Repeat Kinase 2 (LRRK2) is the most commonly mutated gene in familial Parkinson9s disease. LRRK2 is proposed to function in membrane trafficking and co-localizes with microtubules. We report the 3.5Å structure of the catalytic half of LRRK2, and an atomic model of microtubule-associated LRRK2 built using a reported 14Å cryo-electron tomography in situ structure. We propose that the conformation of LRRK29s kinase domain regulates its microtubule interaction, with a closed conformation favoring binding. We show that the catalytic half of LRRK2 is sufficient for microtubule binding and blocks the motility of the microtubule-based motors kinesin and dynein in vitro. Kinase inhibitors that stabilize an open conformation relieve this interference and reduce LRRK2 filament formation in cells, while those that stabilize a closed conformation do not. Our findings suggest that LRRK2 is a roadblock for microtubule-based motors and have implications for the design of therapeutic LRRK2 kinase inhibitors.

TI - Parkinson’s Disease-linked LRRK2 structure and model for microtubule interaction JF - bioRxiv DO - 10.1101/2020.01.06.895367 DA - 2020-01-06 UR - https://www.deepdyve.com/lp/biorxiv/parkinson-s-disease-linked-lrrk2-structure-and-model-for-microtubule-Bn8PbsAhzT SP - 2020.01.06.895367 DP - DeepDyve ER -