Structural analysis of the full-length human LRRK2.

ABSTRACT: 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 specifi

SUBMITTER: Myasnikov A 

PROVIDER: S-EPMC8887629 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature