7lht

Publication Abstract from PubMed

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.

Structural analysis of the full-length human LRRK2.,Myasnikov A, Zhu H, Hixson P, Xie B, Yu K, Pitre A, Peng J, Sun J Cell. 2021 Jun 3. pii: S0092-8674(21)00601-2. doi: 10.1016/j.cell.2021.05.004. PMID:34107286^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.