Related Experiment Video

Updated: Jun 6, 2025

Metabolic Labeling of Leucine Rich Repeat Kinases 1 and 2 with Radioactive Phosphate
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Metabolic Labeling of Leucine Rich Repeat Kinases 1 and 2 with Radioactive Phosphate

Published on: September 18, 2013

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14-3-3 binding maintains the Parkinson's associated kinase LRRK2 in an inactive state

Juliana A Martinez Fiesco, Ning Li, Astrid Alvarez de la Cruz

    Biorxiv : the Preprint Server for Biology
    |November 28, 2024
    PubMed

    Insights

    14-3-3 proteins bind Leucine-rich repeat kinase 2 (LRRK2) to inhibit its activity, crucial for Parkinson's disease (PD) pathogenesis. This structural insight reveals how LRRK2 remains dormant and suggests new PD therapeutic targets.

    Area of Science:

    • Molecular Biology
    • Structural Biology
    • Neuroscience

    Background:

    • Leucine-rich repeat kinase 2 (LRRK2) is implicated in Parkinson's disease (PD) pathogenesis.
    • 14-3-3 proteins are known regulators of LRRK2 activity.

    Purpose of the Study:

    • To determine the structural basis of LRRK2 autoinhibition by 14-3-3 proteins.
    • To investigate the impact of Parkinson's disease-associated mutations on this interaction.

    Main Methods:

    • Cryo-electron microscopy (cryo-EM) to resolve the LRRK2:14-3-3 complex structure.
    • Mutagenesis studies to assess the functional consequences of mutations.

    Main Results:

    • The cryo-EM structure reveals a 14-3-3 dimer stabilizing an autoinhibited LRRK2 monomer.
    • 14-3-3 binding occurs at phosphorylation sites and Roc-COR subdomains, restricting LRRK2 activity.
    • PD-associated mutations weaken 14-3-3 binding, reducing LRRK2 inhibition.

    Conclusions:

    • This study provides a structural mechanism for LRRK2 autoinhibition.
    • Findings illuminate PD biomarker mechanisms and suggest LRRK2-14-3-3 interactions as a therapeutic target for PD.

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