This study investigates the interplay between the GTPase and kinase domains of the Parkinson's disease-associated protein LRRK2. The key findings are:
LRRK2 has a KM value for GTP hydrolysis that lies within the physiological range of cellular GTP concentrations, suggesting its GTPase activity is sensitive to changes in GTP levels.
The Parkinson's disease variants R1441G and G2019S differentially impact the kinetics of LRRK2's GTPase activity, with R1441G showing increased catalytic efficiency and G2019S exhibiting reduced efficiency.
LRRK2 kinase activity negatively regulates the GTPase activity of the Roc domain through an intramolecular feedback mechanism. Autophosphorylation of the Roc P-loop residue T1343 is critical for this regulation.
The T1343A phospho-null mutant disrupts this negative feedback loop, leading to LRRK2 activity comparable to the hyperactive G2019S variant.
This interplay between the GTPase and kinase domains, mediated by autophosphorylation, likely plays an important role in the regulation of LRRK2 signaling and the differential impact of Parkinson's disease mutations.
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biorxiv.org
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by Gilsbach,B. ... om www.biorxiv.org 07-31-2023
https://www.biorxiv.org/content/10.1101/2023.07.31.549909v2Diepere vragen