The In Situ Structure of Parkinson's Disease-Linked LRRK2

Cell. 2020 Sep 17;182(6):1508-1518.e16. doi: 10.1016/j.cell.2020.08.004. Epub 2020 Aug 11.


Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of familial Parkinson's disease. LRRK2 is a multi-domain protein containing a kinase and GTPase. Using correlative light and electron microscopy, in situ cryo-electron tomography, and subtomogram analysis, we reveal a 14-Å structure of LRRK2 bearing a pathogenic mutation that oligomerizes as a right-handed double helix around microtubules, which are left-handed. Using integrative modeling, we determine the architecture of LRRK2, showing that the GTPase and kinase are in close proximity, with the GTPase closer to the microtubule surface, whereas the kinase is exposed to the cytoplasm. We identify two oligomerization interfaces mediated by non-catalytic domains. Mutation of one of these abolishes LRRK2 microtubule-association. Our work demonstrates the power of cryo-electron tomography to generate models of previously unsolved structures in their cellular environment.

Keywords: Parkinson's disease; correlative light and electron microscopy; cryo-electron tomography; integrative modeling; kinase; leucine-rich repeat kinase; microtubule; subtomogram analysis.

Publication types

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

MeSH terms

  • Cryoelectron Microscopy / methods*
  • Cytoplasm / metabolism
  • Electron Microscope Tomography / methods*
  • GTP Phosphohydrolases / chemistry
  • GTP Phosphohydrolases / metabolism
  • HEK293 Cells
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / chemistry*
  • Microscopy, Electron, Transmission
  • Microtubules / chemistry
  • Microtubules / metabolism*
  • Models, Chemical
  • Mutation
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism*
  • Parkinson Disease / pathology
  • Phosphotransferases / chemistry
  • Phosphotransferases / metabolism
  • Protein Domains
  • WD40 Repeats


  • Phosphotransferases
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • GTP Phosphohydrolases