Structural and biochemical basis of ROC-dependent activation of LRRK2.

ABSTRACT: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease, yet the molecular mechanism governing LRRK2 activation remains incompletely understood. LRRK2 is a large multidomain enzyme whose kinase activity is regulated by intramolecular interactions and by its Ras of complex proteins (ROC) GTPase domain. Here, we combine cryo-electron microscopy, X-ray crystallography, and structure-guided biochemical perturbations to define how ROC conformational switching regulates LRRK2 activation. Cryo-EM reconstructions reveal that monomeric full-length LRRK2 samples three distinct conformational states-autoinhibited, intermediate, and activated-indicating that large-scale activation-associated rearrangements can occur through an intrinsic intramolecula

SUBMITTER: Hoang Q 

PROVIDER: S-EPMC12889809 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature