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Assaying the Kinase Activity of LRRK2 in vitro
06:09

Assaying the Kinase Activity of LRRK2 in vitro

Published on: January 18, 2012

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Structure of LRRK2 in Parkinson's disease and model for microtubule interaction

C K Deniston1,2, J Salogiannis1,3, S Mathea4

  • 1Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.

Nature
|August 20, 2020
PubMed

Insights

Leucine-rich repeat kinase 2 (LRRK2) filaments can block motor protein movement on microtubules. Inhibitors stabilizing an open LRRK2 conformation reduce filament formation, offering a therapeutic strategy for Parkinson's disease.

Area of Science:

  • Neuroscience
  • Structural Biology
  • Molecular Biology

Background:

  • Leucine-rich repeat kinase 2 (LRRK2) is a key gene in Parkinson's disease pathogenesis.
  • LRRK2's role in membrane trafficking and microtubule association is established.
  • Limited structural data hinders understanding of LRRK2 function.

Purpose of the Study:

  • To determine the structure of the catalytic half of LRRK2.
  • To model microtubule-associated LRRK2.
  • To elucidate the mechanism of LRRK2-microtubule interaction and its regulation by kinase conformation.

Main Methods:

  • X-ray crystallography or cryo-EM for structural determination.
  • Cryo-electron tomography for in situ structural modeling.
  • In vitro motility assays with purified motors and LRRK2.
  • Cell-based assays to assess LRRK2 filament formation and inhibitor effects.

Main Results:

  • Reported the structure of the catalytic half of LRRK2.
  • Developed an atomic model of microtubule-associated LRRK2.
  • Demonstrated that LRRK2 filaments block kinesin-1 and dynein-1 motility.
  • Showed that kinase inhibitors stabilizing an open conformation reduce LRRK2 filament formation in cells.

Conclusions:

  • LRRK2 conformation regulates its microtubule association and oligomerization.
  • LRRK2 can function as a physical roadblock for microtubule-based motors.
  • Therapeutic strategies targeting LRRK2 conformation may be beneficial for Parkinson's disease.

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