Elucidating the molecular interplay between LRRK2 and Rab GTPases.

Gain-of-function mutations in LRRK2 are a major cause of inherited Parkinson's disease. LRRK2 encodes a multidomain kinase, whose bidirectional interplay with Rab GTPases regulates critical cellular processes like lysosomal homeostasis. Certain Rabs, including Rab12 and Rab29, recruit LRRK2 to organelle membranes and stimulate its kinase activity; activated LRRK2 phosphorylates a subset of Rabs in their Switch-II motifs. Molecular basis governing selective Rab recognition by LRRK2 remains unclear. Here we structurally characterize LRRK2 interactions with representative Rab GTPases and identify three novel Rab-binding sites: site 4 for Rab8A/10, site 5 for Rab43, and site 6 for Rab5A, defining a total of six distinct binding sites that account for known LRRK2-interacting Rabs. Additionally, we elucidated the binding site of GABARAP, an ATG8 member that recruits LRRK2 to stressed lysosomes. Our findings provide a framework for therapeutic targeting of LRRK2 recruitment for Parkinson's.