Molecular Medicine Israel

Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2

Editor’s summary

Mutations in leucine-rich repeat kinase 2 (LRRK2) are implicated in the development of Parkinson’s disease, so this enzyme is a target for therapeutics currently in clinical trials. Zhu et al. determined the structures of LRRK2 bound to Rab29, a membrane-associated protein thought to target the kinase to specific organelles, and found that the resulting complexes adopted several oligomerization states. The largest complex included four copies of LRRK2 in two different conformations: one was similar to the inactive state seen previously and the other represented a proposed active state. Functional experiments and work with mutants provide insight into the structural features of this complex and may inspire new strategies for therapeutic inhibition. —Michael A. Funk


Gain-of-function mutations in LRRK2, which encodes the leucine-rich repeat kinase 2 (LRRK2), are the most common genetic cause of late-onset Parkinson’s disease. LRRK2 is recruited to membrane organelles and activated by Rab29, a Rab guanosine triphosphatase encoded in the PARK16 locus. We present cryo–electron microscopy structures of Rab29–LRRK2 complexes in three oligomeric states, providing key snapshots during LRRK2 recruitment and activation. Rab29 induces an unexpected tetrameric assembly of LRRK2, formed by two kinase-active central protomers and two kinase-inactive peripheral protomers. The central protomers resemble the active-like state trapped by the type I kinase inhibitor DNL201, a compound that underwent a phase 1 clinical trial. Our work reveals the structural mechanism of LRRK2 spatial regulation and provides insights into LRRK2 inhibitor design for Parkinson’s disease treatment.

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