The structural basis for LRRK2's activation and autoinhibition.
The structural basis for LRRK2's activation and autoinhibition.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
San Diego, US · Author affiliation
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.Location evidence
La Jolla, US · Author affiliation
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.Location evidence
San Francisco, US · Author affiliation
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA.Location evidence
Frankfurt am Main, DE · Author affiliation
Institute of Pharmaceutical Chemistry and Structural Genomics Consortium, Goethe-University Frankfurt am Main, Frankfurt, Germany.Location evidence
Salt Lake City, US · Author affiliation
Department of Biochemistry, University of Utah, Salt Lake City, UT 84132, USA.Location evidence
New York City, US · Author affiliation
Institute of Pharmaceutical Chemistry and Structural Genomics Consortium, Goethe-University Frankfurt am Main, Frankfurt, Germany; LRRK2 Investigative Therapeutics Exchange (LITE), New York, NY 10120, USA.Location evidence
Howard, US · Author affiliation
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; LRRK2 Investigative Therapeutics Exchange (LITE), New York, NY 10120, USA.Location evidence
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Original abstract
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the second most common cause of autosomal-dominant Parkinson's disease (PD), and increased LRRK2 kinase activity is also observed in idiopathic PD, making LRRK2 a major actionable therapeutic target. LRRK2 is a 286-kDa multidomain enzyme containing a Ras-like GTPase (ROC) and a kinase domain. Using cryo-electron microscopy (cryo-EM), biochemical reconstitution, and cell-based assays, we show that the ROC GTPase governs switching between autoinhibited and active states: GTP binding promotes activation, whereas GDP binding enforces autoinhibition. Two common PD-linked mutations, G2019S and R1441C/G/H, activate LRRK2 through distinct structural mechanisms, revealing genotype-specific routes to dysregulation. These findings provide a unified framework for understanding LRRK2 regulation with broad therapeutic implications. Stabilizing the guanosine diphosphate (GDP)-bound state may inhibit LRRK2 by maintaining autoinhibition, whereas promoting the GTP-bound state could be advantageous in specific cellular contexts, such as the lung, where increased LRRK2 kinase activity may play protective or regulatory roles.