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

Nature. 2020 Dec;588(7837):344-349. doi: 10.1038/s41586-020-2673-2. Epub 2020 Aug 19.

Abstract

Leucine-rich repeat kinase 2 (LRRK2) is the most commonly mutated gene in familial Parkinson's disease1 and is also linked to its idiopathic form2. LRRK2 has been proposed to function in membrane trafficking3 and colocalizes with microtubules4. Despite the fundamental importance of LRRK2 for understanding and treating Parkinson's disease, structural information on the enzyme is limited. Here we report the structure of the catalytic half of LRRK2, and an atomic model of microtubule-associated LRRK2 built using a reported cryo-electron tomography in situ structure5. We propose that the conformation of the LRRK2 kinase domain regulates its interactions with microtubules, with a closed conformation favouring oligomerization on microtubules. We show that the catalytic half of LRRK2 is sufficient for filament formation and blocks the motility of the microtubule-based motors kinesin 1 and cytoplasmic dynein 1 in vitro. Kinase inhibitors that stabilize an open conformation relieve this interference and reduce the formation of LRRK2 filaments in cells, whereas inhibitors that stabilize a closed conformation do not. Our findings suggest that LRRK2 can act as a roadblock for microtubule-based motors and have implications for the design of therapeutic LRRK2 kinase inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzamides / pharmacology
  • Biocatalysis / drug effects
  • Cryoelectron Microscopy*
  • Dimerization
  • Dyneins / antagonists & inhibitors
  • Dyneins / metabolism
  • Humans
  • Kinesin / antagonists & inhibitors
  • Kinesin / metabolism
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / antagonists & inhibitors
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / chemistry*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / ultrastructure
  • Microtubules / chemistry*
  • Microtubules / metabolism*
  • Microtubules / ultrastructure
  • Models, Molecular
  • Movement / drug effects
  • Parkinson Disease / metabolism*
  • Protein Binding
  • Protein Domains / drug effects
  • Pyrazoles / pharmacology
  • WD40 Repeats

Substances

  • 3-((1H-pyrazolo(3,4-b)pyridin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide
  • Benzamides
  • Pyrazoles
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Dyneins
  • Kinesin