Structural analysis of the full-length human LRRK2

Mutations in leucine-rich repeat kinase 2 (LRRK2) are commonly implicated in the pathogenesis of both familial and sporadic Parkinson's disease (PD). LRRK2 regulates critical cellular processes at membranous organelles and forms microtubule-based pathogenic filaments, yet the molecular basis underlying these biological roles of LRRK2 remains largely enigmatic. Here, we determined high-resolution structures of full-length human LRRK2, revealing its architecture and key interdomain scaffolding elements for rationalizing disease-causing mutations. The kinase domain of LRRK2 is captured in an inactive state, a conformation also adopted by the most common PD-associated mutation, LRRK2(G2019s). This conformation serves as a framework for structure-guided design of conformational specific inhibitors. We further determined the structure of COR-mediated LRRK2 dimers and found that single-point mutations at the dimer interface abolished pathogenic filamentation in cells. Overall, our study provides mechanistic insights into physiological and pathological roles of LRRK2 and establishes a structural template for future therapeutic intervention in PD.

Automated summary

Mutations in LRRK2 are commonly associated with Parkinson's disease. This study provides insights into the physiological and pathological roles of LRRK2, and establishes a structural template for future therapeutic interventions in PD. The high-resolution structures of full-length human LRRK2 and COR-mediated LRRK2 dimers reveal key elements for rationalizing disease-causing mutations and potential targets for inhibitors.