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Assaying the Kinase Activity of LRRK2 in vitro
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LRRK2 autophosphorylation enhances its GTPase activity.

Zhiyong Liu1, James A Mobley1, Lawrence J DeLucas1

  • 1*Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, Center for Structural Biology, Department of Optometry, and Department of Surgery, The University of Alabama at Birmingham, Birmingham, Alabama, USA; and Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, USA.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|September 24, 2015
PubMed
Summary

Leucine-rich repeat kinase 2 (LRRK2) kinase phosphorylates its own GTPase domain, enhancing GTP hydrolysis and promoting dimer formation. This discovery reveals a novel kinase-mediated control mechanism for GTPase activity.

Keywords:
G-proteinGTP-hydrolysisParkinson diseaseROCphosphorylation

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Neuroscience

Background:

  • Leucine-rich repeat kinase 2 (LRRK2) mutations cause Parkinson disease.
  • GTPase proteins typically modulate kinases, but LRRK2's kinase domain phosphorylates its own GTPase domain.

Purpose of the Study:

  • To investigate the mechanism of LRRK2 autophosphorylation and its effect on GTPase activity.
  • To explore the role of the ameba LRRK2 ortholog ROCO4 in phosphorylating the human LRRK2 GTPase domain.

Main Methods:

  • Biochemical assays to measure GTP hydrolysis rates and dissociation kinetics.
  • Modeling experiments to analyze conformational changes.
  • Bioinformatic analysis of LRRK2 phosphorylation sites against phosphoproteome data.

Main Results:

  • ROCO4 phosphorylates the human LRRK2 Ras-of-complex (ROC) domain on key residues.
  • Phosphorylation significantly enhances ROC's GTP hydrolysis rate.
  • Phosphorylation promotes ROC dimer formation and induces conformational changes in the p-loop structure.

Conclusions:

  • LRRK2 kinase phosphorylates its own GTPase domain, a novel mechanism for regulating GTPase activity.
  • This autophosphorylation impacts GTP hydrolysis and protein structure.
  • Findings suggest a broader role for kinase-mediated phosphorylation in regulating GTPase function across various proteins.