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Structure of LRRK2 in Parkinson’s disease and model for microtubule interaction

Abstract

Leucine-rich repeat kinase 2 (LRRK2) is the most commonly mutated gene in familial Parkinson’s disease (PD)1 and is also linked to its idiopathic form2. LRRK2 is proposed to function in membrane trafficking3 and co-localizes with microtubules4. Despite LRRK2’s fundamental importance for understanding and treating PD, there is limited structural information on it. Here 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 structure5. We propose that the conformation of LRRK2’s kinase domain regulates its microtubule interaction, with a closed conformation favouring oligomerization on microtubules. We show that the catalytic half of LRRK2 is sufficient for filament formation and blocks the motility of the microtubule-based motors kinesin-1 and cytoplasmic dynein-1 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 can act as a roadblock for microtubule-based motors and have implications for the design of therapeutic LRRK2 kinase inhibitors.

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Correspondence to S. L. Reck-Peterson or A. E. Leschziner.

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Supplementary Figure 1

Western blots shown in Extended Data Fig. 9.

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Video 1

| LRRK2RCKW Structure Overview of the cryo-EM structure of LRRK2RCKW with close-ups of its domains.

Video 2

| Parkinson’s Disease mutations in LRRK2RCKW Structure Close-ups of the residues most commonly mutated in PD. I2020 (mutated to T2020 in PD) is disordered in our structure and this is indicated by the square brackets around its name.

Video 3

| The C-terminal helix of LRRK2RCKW Close-up of the C-terminal helix of LRRK2RCKW showing the residues involved in electrostatic and hydrophobic interactions between it and the kinase domain.

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Deniston, C.K., Salogiannis, J., Mathea, S. et al. Structure of LRRK2 in Parkinson’s disease and model for microtubule interaction. Nature (2020). https://doi.org/10.1038/s41586-020-2673-2

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