Parkinson's Disease-linked LRRK2 structure and model for microtubule interaction

Deniston, C. K.; Salogiannis, J.; Mathea, S.; Snead, D. M.; Lahiri, I.; Donosa, O.; Watanabe, R.; Böhning, J.; Shiau, A. K.; Knapp, S.; Villa, E.; Reck-Peterson, S. L.; Leschziner, A. E.

doi:10.1101/2020.01.06.895367

bioRxiv · 10.1101/2020.01.06.895367

Parkinson's Disease-linked LRRK2 structure and model for microtubule interaction

Deniston, C. K.·Salogiannis, J.·Mathea, S.·Snead, D. M.·Lahiri, I.·Donosa, O.·Watanabe, R.·Böhning, J.·Shiau, A. K.·Knapp, S.·Villa, E.·Reck-Peterson, S. L.·Leschziner, A. E.

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Abstract

Leucine Rich Repeat Kinase 2 (LRRK2) is the most commonly mutated gene in familial Parkinsons disease. LRRK2 is proposed to function in membrane trafficking and co-localizes with microtubules. We report the 3.5[A] structure of the catalytic half of LRRK2, and an atomic model of microtubule-associated LRRK2 built using a reported 14[A] cryo-electron tomography in situ structure. We propose that the conformation of LRRK2s 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.

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Deniston, C. K., Salogiannis, J., Mathea, S., Snead, D. M., Lahiri, I., Donosa, O., Watanabe, R., Böhning, J., Shiau, A. K., Knapp, S., Villa, E., Reck-Peterson, S. L., Leschziner, A. E.. 2020-01-06. Parkinson's Disease-linked LRRK2 structure and model for microtubule interaction. https://doi.org/10.1101/2020.01.06.895367

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