Related Experiment Video

Updated: Jul 7, 2025

Metabolic Labeling of Leucine Rich Repeat Kinases 1 and 2 with Radioactive Phosphate
11:31

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

Published on: September 18, 2013

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Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2

Hanwen Zhu1, Francesca Tonelli2,3, Martin Turk4

  • 1Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Science (New York, N.Y.)
|December 21, 2023
PubMed

Insights

Gain-of-function mutations in leucine-rich repeat kinase 2 (LRRK2) cause Parkinson's disease. New structures reveal how Rab29 activates LRRK2, offering insights for developing LRRK2 inhibitors to treat Parkinson's disease.

Area of Science:

  • Neuroscience
  • Structural Biology
  • Genetics

Background:

  • Gain-of-function mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of late-onset Parkinson's disease.
  • LRRK2 activation is spatially regulated and involves recruitment to membrane organelles by Rab29, a Rab GTPase.

Purpose of the Study:

  • To elucidate the structural mechanism of LRRK2 activation by Rab29.
  • To provide insights into LRRK2 inhibitor design for Parkinson's disease.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was used to determine the structures of Rab29-LRRK2 complexes.
  • Analysis of three distinct oligomeric states captured during LRRK2 recruitment and activation.

Main Results:

  • Rab29 induces a novel tetrameric assembly of LRRK2, comprising two active central protomers and two inactive peripheral protomers.
  • The active LRRK2 protomers in the tetramer resemble the conformation targeted by type I kinase inhibitors like DNL201.

Conclusions:

  • The study reveals the structural basis for LRRK2 spatial regulation by Rab29.
  • These findings offer critical insights for the rational design of LRRK2 inhibitors for Parkinson's disease therapeutics.

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